WO2006133353A2 - Methods of facilitating neural cell survival using non-peptide and peptide bdnf neurotrophin mimetics - Google Patents

Methods of facilitating neural cell survival using non-peptide and peptide bdnf neurotrophin mimetics Download PDF

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WO2006133353A2
WO2006133353A2 PCT/US2006/022268 US2006022268W WO2006133353A2 WO 2006133353 A2 WO2006133353 A2 WO 2006133353A2 US 2006022268 W US2006022268 W US 2006022268W WO 2006133353 A2 WO2006133353 A2 WO 2006133353A2
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alkyl
aralkyl
aryl
compound
independently selected
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WO2006133353A3 (en
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Frank M. Longo
Stephen M. Massa
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The University Of North Carolina At Chapel Hill
The Regents Of The University Of California
U.S. Government represented by the Department of veterans Affairs
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Priority to EP06784665A priority Critical patent/EP1893192A4/en
Priority to JP2008515915A priority patent/JP5461009B2/en
Publication of WO2006133353A2 publication Critical patent/WO2006133353A2/en
Publication of WO2006133353A3 publication Critical patent/WO2006133353A3/en

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    • A61K38/18Growth factors; Growth regulators
    • A61K38/185Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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    • C07K5/1016Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the presently disclosed subject matter generally relates to the treatment of disorders in a subject, including but not limited to neurological disorders. More particularly, the methods of the presently disclosed subject matter relate to administering to a subject an effective amount of a compound having binding and/or modulation specificity for the TrkB receptor molecule to treat a disorder in the subject.
  • Neurotrophins are polypeptides that play a role in the development, function, and/or survival of certain cells, including neurons. The death or dysfunction of neurons has been directly implicated in a number of neurological disorders. It has been suggested that alterations in neurotrophin localization, expression levels of neurotrophins, and/or expression levels of the receptors that bind neurotrophins are linked to neuronal degeneration or dysfunction. This degeneration or dysfunction can occur in the neurological disorders Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis (ALS), among others. Neurotrophins also mediate fundamental mechanisms relevant to non- neurological disorders including for example depression, obesity, and ischemic conditions of peripheral tissues.
  • ALS amyotrophic lateral sclerosis
  • Neurotrophins include Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5), Neurotrophin 6 (NT-6) and Brain Derived Neurotrophic Factor (BDNF).
  • NGF Nerve Growth Factor
  • NT-3 Neurotrophin-3
  • NT-4/5 Neurotrophin-4/5
  • NT-6 Neurotrophin 6
  • BDNF Brain Derived Neurotrophic Factor
  • Neurotrophins are found in both precursor form, known as pro- neurotrophins, and in mature form.
  • the mature forms are proteins of about 120 amino acids in length that exist in physiological states as stable, non- covalent approximately 25 kDa homodimers.
  • Each neurotrophin monomer includes three solvent-exposed ⁇ -hairpin loops, referred to as loops 1 , 2, and 4 that exhibit relatively high degrees of amino acid conservation across the neurotrophin family.
  • Mature neurotrophins bind preferentially to the receptors Trk and p75 NTR , while pro-neurotrophins, which contain an N-terminal domain proteolytically removed in mature forms, interact principally with the p75 NTR receptor and through their N-terminal domains, with the sorting receptor sortilin (Fahnestock, M., Michalski, B., Xu, B., Couqhlin, M.D. (2001 ) MoI
  • the p75 NTR receptor interacts with Trks and modulates Trk signaling, but is also independently coupled to several signaling systems, including pro-survival signals, IRAK/TRAF ⁇ /NF ⁇ -B, PI3/AKT, and pro-apoptotic signals, NRAGE/JNK (Mamidipudi, V., Li. X., Wooten, M.W. (2002) J Biol Chem 277, 28010-28018; Roux, P.P..
  • p75 NTR promotes cell survival or death.
  • proNGF induces death of superior cervical ganglion neurons and oligodendrocytes through p75 NTR , and its comitant binding to p75 NTR and sortilin has been shown to activate cell death pathways (Nvkiaer. A. et al., (2004) Nature 427, 843-848; Lee. R., Kermani, P.. Teng. K.K., Hempstead, B.L (2001 ) Science 294, 1945-1948; Beattie. M.S., et al. (2002) Neuron 36, 375-386).
  • neurotrophins When administered for therapeutic use, neurotrophins exhibit suboptimal pharmacological properties, including poor stability with low serum half lives, likely poor oral bioavailability, and restricted central nervous system penetration (Podulso, J. F., Curran, G. L. (1996) Brain Res MoI Brain Res 36, 280-286; Saltzman, W.M., Mak, M.W., Mahonev, M.J., Duenas, E.T.. Cleland, J.L (1999) Pharm Res 16, 232-240; Partridge. W. M. (2002) Adv Exp Med Bio 513, 397-430). Additionally, the highly pleiotropic effects of neurotrophins achieved through action of the triple receptor signaling network increases the chances of adverse effects.
  • the disorder is selected from the group consisting of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Rett syndrome, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications, motor neuron disease, multiple sclerosis, HIV dementia, peripheral nerve injury, hearing loss, depression, obesity, metabolic syndrome, pain, cancer, and conditions involving degeneration or dysfunction of cells expressing TrkB.
  • the subject is a human subject.
  • Also disclosed herein are methods of facilitating neural cell survival or promoting neural function comprising treating a neural cell with a compound having the ability to specifically bind and/or modulate the activity of a TrkB receptor molecule.
  • TrkB receptor molecule compounds having binding and/or modulation specificity for a TrkB receptor molecule.
  • the compound having binding and/or modulation specificity for a TrkB receptor molecule is a mimetic of a BNDF /?-turn loop.
  • the compound comprises a pharmacophore substantially identical to the pharmacophore illustrated in Figure 1.
  • the compound is a small molecule or small peptide.
  • the BNDF /?-tum loop is loop 2.
  • the loop 2 BDNF mimetic compound has a structure of Formula (I):
  • R-i, R 2 , and R 3 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryioxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
  • X 1 and X 2 are independently selected from CH 2 and NR 4 , wherein R 4 is selected from H, alkyl, aralkyl, and aryl; and
  • Di is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
  • R 5 and R 6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt.
  • the compound of Formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the loop 2 BDNF mimetic compound has a structure of Formula (II):
  • L 1 and L 3 are independently selected from the group consisting of CrC 5 alkylene, arylene, aralkylene, and substituted arylene;
  • L 2 is selected from the group consisting of C 1 -C 5 alkylene, arylene, aralkylene, substituted arylene,
  • L 4 is C 1 -C 5 alkylene
  • Zi, Zz 1 and Z 3 are independently selected from the group consisting of H, alkyl, aryl, and aralkyl;
  • X 3 , X 4 , X 5 , and X 6 are independently N or CH;
  • Yi, Y2, and Y3 are independently carbonyl, sulfonyl, or methylene;
  • D 2 , D 3 , D 4 , and D 5 are independently selected from H, alkyl, halo, hydroxy!, mercapto, mercaptoalkyl, alkoxyl, aryloxyl, aralkoxyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is selected from the group consisting of:
  • the loop 2 BDNF mimetic compound has a structure of Formula (III):
  • l_ 5 is present or absent, and when present is C-i-Csalkylene;
  • Xr and X 8 are independently N or CH;
  • Rio and Rn are independently selected from the group consisting of H, halo, alky), and cyano;
  • D 6 , D 7 , and Da are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , R 6 , R j , Ra, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (III) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • the loop 2 BDNF mimetic has a structure of Formula (IV):
  • Xg and X 10 are independently CH 2 or NR 4 , wherein R 4 is selected from H, alkyl, aralkyl and aryl;
  • R- I2 is selected from the group consisting of H, alkyl, aralkyl, aryl, acyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
  • R- 13 is selected from H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkycarbamoyl, and dialkylcarbamoyl;
  • Ru and R 15 are independently selected from H alkyl, substituted alkyl, and aralkyl
  • Ri 6 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
  • R 5 and R 6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (IV) is or a stereoisomer thereof.
  • the loop 2 BDNF mimetic compound has a structure of Formula (V):
  • Le and L 7 are independently present or absent, and if present are C-I-C 5 alkylene;
  • Xii is O, S, CH 2 or NR 17 , wherein Ri 7 is selected from H, alkyl, aralkyl and aryl;
  • X 12 , Xi3, and X 14 are independently CH or N;
  • X-I 5 is selected from the group consisting of O, S, and NR 18 , wherein R 1 S is selected from H, alkyl, aralkyl, and aryl; and
  • Dg, D 1O , D 11 , and D 12 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R5, RQ, R 7 , Rs, and R 9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (V) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (Vl):
  • L 8 is present or absent, and when present is C 1 -C 5 alkylene;
  • X- I6 is selected from the group consisting of O, S, and NRi 9 , wherein R 19 is selected from H, alkyl, aralkyl and aryl;
  • X-I 7 is selected from the group consisting of O, S, CH 2 , and NR20, wherein R20 is selected from H, alkyl, aralkyl, and aryl;
  • Xi 8 and X 19 are independently selected from N and CH; and D-1 3 and Du are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R5, RQ, R 7 , RS, and R 9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the loop 2 BDNF mimetic compound has a structure of Formula (VII):
  • m and n are independently 1 or 2; each Lg and L 10 can be present or absent, and when present is C 1 -C 5 alkylene;
  • X20 and X21 are independently selected from CH, CH2, N, and NR 4 , wherein R 4 is selected from H, alkyl, aralkyl and aryl;
  • X22 is selected from H and halo; and each Di 5 and each Di 6 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (VII) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the loop 2 BDNF mimetic compound has a structure of Formula (VIII):
  • Li 1 is present or absent, and when present is C 1 -C 5 alkylene;
  • X 23 is N or CH;
  • F?2i and R 2 2 are independently selected from the group consisting of H, alkyl, aralkyl, aryl and halo; and
  • D 17 , D 18 , and D 19 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 6 , R7, Re, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (VIII) is selected from the group consisting of:
  • the loop 2 BDNF mimetic compound has a structure of Formula (IX):
  • L 12 is present or absent, and when present is CrC 5 alkylene
  • X 24 is N or CH
  • R2 3 is selected from the group consisting of H, alkyl, aralkyl, aryl, and halo;
  • O20, D 2 -I, D22, D23, and D2 3 are independently selected from H 1 alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyioxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (IX) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the loop 2 BDNF mimetic compound has a structure of Formula (X):
  • X25 and X26 are selected from N and CH;
  • X2 7 is selected from N, CH, CH2, and NR2 5 , wherein R2 5 is H or alkyl;
  • R24 is selected from H, alkyl, aralkyl, aryl, and halo
  • D2 5 and each D2 6 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , Re, R7, Rs, and R 9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (X) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the loop 2 BDNF mimetic compound has a structure of Formula (Xl):
  • X28 is selected from CH 2 , O, S, and NR26, wherein R26 is selected from H, alkyl, aralkyl, and aryl;
  • X 29 is N or CH
  • X 3 0 is CH 2 or NR2 7 ; wherein R 27 is selected from H, alkyl, aralkyl, and aryl;
  • X 31 is N or CH
  • D27, D 2 8, and D 29 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, wherein R5, Re, R7, Rs, and R 9 are independently selected from H, alky), aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (Xl) is
  • the compound is a derivative of a parent compound having binding and/or modulation specificity for a TrkB receptor molecule, wherein the derivative also has binding and/or modulation specificity for the TrkB receptor or wherein the derivative is modified in vivo to form a compound having binding and/or modulation specificity for the TrkB receptor.
  • the derivative exhibits an enhancement in at least one of the characteristics selected from the group consisting of potency, selectivity, hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound.
  • An object of the presently disclosed subject matter is to provide methods of and compositions for facilitating neural cell survival or promoting the function of neurons or other TrkB-bearing cells using BDNF small molecule mimetics.
  • Figure 1 is a ribbon representation of the X-ray crystal structure of a portion of human BDNF peptide including loop 2.
  • Hydrogen bonding features are represented by pairs of spheres with their relative positions indicating the locations of the acceptor and donor. One of the spheres of each pair is centered on putative acceptor/donor features in the model, while the other (i.e., the sphere centered on the pointed end of the arrow) indicates the target location of a complementary feature on any potentially interacting molecule.
  • the diameter of the spheres represents a spatial tolerance for chemical feature matching in 3D conformer library scans.
  • Figure 2 is a series of fluorescence photomicrographs of E16 mouse hippocampal neuronal cultures treated with culture medium only (CM) or medium containing BDNF or Compound 4 (also referred to in the figures as
  • LM22A-4 and BD2-4 showing that Compound 4 has neurotrophic effects similar to that of BDNF. Neurons are immunostained with GAP43 antibody.
  • Figures 3A-3E are a series of neuron survival dose response curves of BDNF (Figure 3A), Compound 1 (also referred to as BD2-1 , Figure 3B) Compound 2 (also referred to as BD2-2, Figure 3C), Compound 3 (also referred to as BD2-3, Figure 3D), and Compound 4 (also referred to as BD2- 4, Figure 3E) using Mouse E16 hippocampal neurons. Survival was determined as the total number of cells in each well that were both morphologically intact and filled with blue formazan MTT conversion product (Lonqo, F. M., Manthorpe, M., Xie, Y.M., and Varon, S. (1997) J Neurosci Res. 48, 1-17).
  • FIG. 4 is a bar graph comparing neuron survival (Mouse E16 hippocampal neurons) with no treatment (CM), treatment with BDNF (50 ng/mL), with Compound 4 (BD2-4), or with a combination of BDNF and Compound 4 (BDNF + BD2-4), showing that Compound 4 is a partial agonist of BDNF. This is the first observation that a small moleucle BDNF mimetic can function as a partial agonist.
  • Figure 5A is a digital composite image of Western blots monitoring Trk activation as indicated by promotion of Trk phosphorylation at Y490 in NIH3T3 cells expressing either TrkB (upper two panels) or TrkA (lower two panels) demonstrating that BDNF and Compound 4 (BD2-4) (as indicated above each lane in the blots) activate TrkB and not TrkA while NGF (second column from left) activates TrkA but not TrkB.
  • the upper lane for each pair shows staining with anti-p-Trk Y490 antibody (p-Trk Y490 ), while the lower lane of each pair shows total TrkB or TrkA.
  • CM represents culture medium.
  • Figure 5B is a digital composite image of Western blots monitoring TrkC activation as indicated by promotion of Trk phosphorylation at Y490 in NIH3T3 cells expressing TrkC.
  • BDNF and Compound 4 (BD2-4) (the right two lanes) do not activate TrkC, while NT-3 (second lane from the left) activates TrkC.
  • CM represents culture medium.
  • Figure 6A is a bar graph showing prevention of quinolinic acid- induced death of mouse E16 striatal neurons by varying concentrations of BDNF and Compound 4 (BD2-4).
  • the quinolinic acid-induced death is used as a model for neuronal death in Huntington's disease (HD).
  • HD Huntington's disease
  • Application of quinolininc acid at 7.5 mM leads to death of approximately 50% of neurons as seen comparing culture medium alone (CM) to quinolinic acid in the absence of BDNF. Bars indicate mean ⁇ s.e.m.
  • Figure 6B is a bar graph showing the effects of K252a (a TrkB receptor activation inhibitor) on the prevention of quinolinic acid-induced death in mouse E16 striatal neurons by BDNF and Compound 4 (BD2-4).
  • CM represents culture medium and QUIN represents quinolinic acid. Bars indicate mean ⁇ s.e.m and *** indicates p ⁇ 0.005 student t test.
  • Figure 6C is a bar graph of the results of a study similar to that described for Figure 6B only using Darp32-positive neurons. Bars indicate mean ⁇ s.e.m and *** indicates p ⁇ 0.005 student t test.
  • Figure 7 is a bar graph showing that BDNF mimetics prevent neuronal death in a Parkinson's disease (PD) model.
  • PD Parkinson's disease
  • the TrkB inhibitor K252a has a small effect on lowering cell survival in the SH-SY5Y neuroblastoma cells compared to cells treated with culture medium (CM) alone.
  • CM culture medium
  • the neurotoxin 1-methyl-4-phenylpyridinium (MPP + , 100 ⁇ M) promotes death of essentially all cells.
  • Figure 8 is a bar graph showing that BDNF and BDNF mimetics prevent A/?-induced neuronal degeneration in E16-17 hippocampal neurons. Neuronal cell survival in culture medium (CM) and with the addition of 10 ⁇ M A/?s c ram b i e d oligomer are shown in the two bars on the left-hand side of the graph as positive controls.
  • CM culture medium
  • Cells were also treated with 10 ⁇ M A#i -42 alone or in combination with NGF (lOOng/mL), NGF mimetic LM11A-31 (100 nM), a combination of NGF and LM11A-31 , Compound 4 (BD2-4, 500 nM), Compound 24 (BD2-24, 500 nM), or either 20 or 100 ng/mL BDNF, as indicated under each bar.
  • Addition of A/?i -42 oligomer but not control A/?s c r a m b i ed oligomer resulted in an approximate 40% reduction in neuronal survival.
  • BDNF mimetics BD2-4 and BD2-24 were as effective as BDNF in blocking A/?-induced degeneration. Mean + SE are shown and *** p ⁇ 0.001 for survival above CM baseline.
  • alterations in neurotrophin localization, expression levels of neurotrophins, and/or expression levels of the receptors that bind neurotrophins can occur. Accordingly, by providing subjects suffering from such disorders with a corresponding neurotrophic factor or mimetic thereof, such neural degeneration can be alleviated or prevented. In some cases, inhibition of neurotrophin function would be of benefit.
  • methods of treating a disorder and/or facilitating neural cell survival by administering a non-peptide compound having binding and/or modulation specificity for the TrkB receptor molecule are provided.
  • the methods and compounds of the presently disclosed subject matter relate to compounds having binding and/or modulation specificity for the TrkB receptor molecule.
  • discovery by in silico screening of compounds having binding and/or modulation specificity for the TrkB receptor are suitable for positively regulating survival or function of neural and other cells.
  • the compounds can promote survival signaling.
  • neurological disorder includes any disorder characterized by damage of nervous system cells and include the following, without limitation, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications complications, multiple sclerosis, peripheral nerve injury, and conditions involving degeneration or dysfunction of cells expressing Trkb.
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications complications, multiple sclerosis, peripheral nerve injury, and conditions involving degeneration or dysfunction of cells expressing Trkb.
  • alkyl refers to Ci -2 o inclusive, linear ⁇ i.e., "straight-chain”), branched, or cyclic (a “cycloalkyl”), saturated or at least partially and in some cases fully unsaturated ⁇ i.e., alkenyl and alkynyl) hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te/Y-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, methylpropynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups.
  • Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • Lower alkyl refers to an alkyl group having 1 to about 8 carbon atoms ⁇ i.e., a C-i-s alkyl), e.g., 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Higher alkyl refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • alkyl refers, in particular, to C- ⁇ _ 8 straight-chain alkyls.
  • alkyl refers, in particular, to Ci -8 branched-chain alkyls.
  • Alkyl groups can optionally be substituted (a "substituted alkyl") with one or more alkyl group substituents, which can be the same or different.
  • alkyl group substituent includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
  • alkyl chain There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl”), or aryl.
  • substituted alkyl includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
  • alkyl and/or substituted alkyl include an “allyl” or an “allylic group.”
  • alkyl and/or substituted alkyl include allyl groups, such as but not limited to, allyl, methylallyl, di-methylallyl, and the like.
  • allylic position or “allylic site” refers to the saturated carbon atom of an allylic group.
  • a group, such as a hydroxyl group or other substituent group, attached at an allylic site can be referred to as "allylic.”
  • aryl is used herein to refer to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety.
  • the common linking group also can be a carbonyl, as in benzophenone, or oxygen, as in diphenylether, or nitrogen, as in diphenylamine.
  • aryl specifically encompasses heterocyclic aromatic compounds.
  • the aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others.
  • aryl means a cyclic aromatic comprising about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings.
  • the aryl group can be optionally substituted (a "substituted aryl") with one or more aryl group substituents, which can be the same or different, wherein "aryl group substituent” includes alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and -NR 1 R", wherein R' and R" can each be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.
  • substituted aryl includes aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
  • aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, fluorene, and the like.
  • ring structure for example, but not limited to a
  • n one (1 ) comprises compound groups including:
  • a dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
  • Alkylene refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • the alkylene group can be straight, branched or cyclic.
  • the alkylene group also can be optionally unsaturated and/or substituted with one or more "alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
  • An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons.
  • Arylene refers to a bivalent aryl group.
  • An exemplary arylene is phenylene, which can have ring carbon atoms available for bonding in ortho, meta, or para positions with regard to each other, i.e.,
  • the arylene group can also be napthylene or a divalent fluorene moiety.
  • the arylene group can be optionally substituted (a "substituted arylene") with one or more "aryl group substituents" as defined herein, which can be the same or different.
  • “Aralkylene” refers to a bivalent group that contains both alkyl and aryl groups.
  • aralkylene groups can have two alkyl groups and an aryl group (i.e., -alkyl-aryl-alkyl-), one alkyl group and one aryl group (i.e., - alkyl-aryl-) or two aryl groups and one alkyl group (i.e., -aryl-alkyl-aryl-)
  • acyl refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent (i.e., as represented by RCO — , wherein R is an alkyl, aralkyl, or aryl group as defined herein).
  • RCO substituent
  • acyl specifically includes arylacyl groups, such as an acetylfuran and a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl.
  • Cyclic and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the cycloalkyl group can be optionally partially unsaturated.
  • the cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group.
  • Representative monocyclic cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the cycloalkyl group can be optionally substituted with a linking group, such as an alkyiene group as defined hereinabove, for example, methylene, ethylene, propylene, and the like.
  • the cycloalkyl group can be referred to as, for example, cyclopropylmethyl, cyclobutylmethyl, and the like.
  • multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl.
  • Alkoxyl or “alkoxy” refer to an alkyl-O- group wherein alkyl is as previously described.
  • alkoxyl as used herein can refer to C 1 -20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo- hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, £-butoxyl, and pentoxyl.
  • Aryloxyl refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl.
  • aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
  • Aralkyl refers to an aryl— alkyl— group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
  • aralkoxyl refers to an aralkyl-0 group wherein aralkyl is as described above.
  • “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described.
  • An exemplary aralkyloxyl group is benzyloxyl.
  • Alkylamino refers to an -NHR group wherein R is an alkyl group or substituted alkyl group as previously described.
  • Dialkylamino refers to an -NRR' group wherein each of R and R' is independently an alkyl group and/or a substituted alkyl group as previously described.
  • Exemplary dialkylamino groups include ethylmethylamino, dimethylamino, and diethylamino.
  • Alkoxycarbonyl refers to an alkyl-O-CO- group.
  • exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and if-butyloxycarbonyl.
  • Aryloxycarbonyl refers to an aryl-O-CO- group.
  • exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
  • Alkoxycarbonyl refers to an aralkyl-O-CO- group.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
  • Carbamoyl refers to an H 2 N-CO- group.
  • Alkylcarbamoyl refers to a R 1 RN-CO- group wherein one of R and R 1 is hydrogen and the other of R and R' is alkyl and/or substituted alkyl as previously described.
  • Dialkylcarbamoyl refers to a R 1 RN-CO- group wherein each of R and R 1 is independently alkyl and/or substituted alkyl as previously described.
  • acyloxyl refers to an acyl-O- group wherein acyl is as previously described.
  • acylamino refers to an acyl-NH- group wherein acyl is as previously described.
  • alkenylene denotes an acyclic carbon chain (i.e., having an open-chain structure) having a carbon-to-carbon double bond and is represented by the formula C n H 2n- 2, which optionally can be substituted one or more times.
  • Representative alkenylene groups include, but are not limited to, ethenylene, propenylene, 1- or 2-butenylene, 1-, or 2-pentylene, and the like.
  • Aroylamino refers to an aroyl-NH- group wherein aroyl is as previously described.
  • amino refers to the -NH 2 group.
  • cyano refers to the -CN group.
  • halo refers to fluoro, chloro, bromo, and iodo groups.
  • hydroxyl refers to the -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with an - OH group.
  • mercapto refers to the -SH group.
  • mercaptoalkyl refers to the -SR group wherein R is alkyl or substituted alkyl.
  • oxo refers to a compound described previously herein wherein a carbon atom is replaced by an oxygen atom.
  • nitro refers to the -NO 2 group.
  • thio refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
  • sulfate refers to the -SO 4 group.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing one or more rings, for example, one ring, two rings, three rings, or four rings, with three or more carbon atoms per ring, for example, 3, 4, 5, 6, 7, or 8 carbon atoms per ring.
  • exemplary cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
  • substituted cycloalkenyl refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 , 2, 3, or 4 substituents, at any available point of attachment.
  • substituents include, but are not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
  • R groups such as groups Ri and R 2 , or groups X and Y
  • substituents being referred to can be identical or different.
  • Ri and R 2 can be substituted alkyls, or Ri can be hydrogen and R 2 can be a substituted alkyl, and the like.
  • treatment covers any treatment of a disease, disorder, and/or condition in an animal or mammal, particularly a human, and includes: (i) preventing a disease, disorder and/or condition from occurring in a person which can be predisposed to the disease, disorder and/or condition, or at risk for being exposed to an agent that can cause the disease, disorder, and/or condition; but, has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder and/or condition, i.e., arresting its development; and (iii) relieving the disease, disorder and/or condition, i.e., causing regression of the disease, disorder and/or condition.
  • mimetic refers to a compound having similar functional and/or structural properties to another known compound or a particular fragment of that known compound, such as a known compound of biological origin, e.g., a polypeptide or fragment thereof.
  • Binding specificity refers to the ability of a protein or other type of molecule capable of recognizing and interacting with a complementary site on another protein or other type of molecule.
  • binding specificity can refer to the ability of a molecule to bind preferentially to one type of molecule over another.
  • binding specificity can refer the ability of a BDNF mimetic to preferentially bind to TrkB as opposed to TrkA or TrkC.
  • a molecule having binding specificity for a receptor can be used for one or more of contacting the receptor, activating the receptor, and inhibiting the receptor.
  • modulation specificity refers to a molecule that can modulate the activity of one receptor preferentially.
  • the molecule can modulate the activity of one receptor to a greater extent than another receptor or can modulate the activity of one receptor in a group of receptors exclusively.
  • a BDNF mimetic can specifically modulate the activity of TrkB and not TrkA or TrkC.
  • the modulation of activity can include, but is not limited to, upregulation, downregulation, activation, partial activation, agonism, partial agonism, antagonism, partial antagonism, inhibition, partial inhibition, or a combination thereof.
  • a molecule having modulation specificity for a receptor can be used, for example, to contact and activate a receptor or to contact and inhibit a receptor.
  • binding and/or modulation specificity refers to a molecule that can bind a designated receptor, modulate the activity of a designated receptor, or both bind and modulate the activity of a designated receptor.
  • pharmacophore refers to a molecular moiety capable of exerting a selected biochemical effect, e.g., inhibition of an enzyme, binding to a receptor, chelation of an ion, and the like.
  • a selected pharmacophore can have more than one biochemical effect, e.g., can be an inhibitor of one enzyme and an agonist of a second enzyme.
  • a therapeutic agent can include one or more pharmacophores, which can have the same or different biochemical activities.
  • derivative refers to a compound chemically modified so as to differentiate it from a parent compound. Such chemical modifications can include, for example, replacement of hydrogen by an alkyl, acyl, or amino group.
  • a derivative compound can be modified by, for example, glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the compound from which it was derived.
  • small molecule and small peptide refer to compounds having molecular weights below 1000.
  • the small molecule or small peptide is a compound having a molecular weight below 750.
  • the small molecule or small peptide has a molecular weight below 500.
  • amino acid residue refers to the radical or diradical of one of the 20 standard amino acids or of a nonstandard amino acid that results from the loss of a proton from the amine group, the loss of the hydroxyl from the carboxylic acid group, or the loss of both a proton from the amine group and the hydroxyl from the carboxylic acid group.
  • peptide also refers to derivatives of peptides wherein the amino terminus, the carboxyl terminus, one or more amino acid side chain, or a combination thereof has been chemically modified or derivatized, for example, through acylation, alkylation, reduction, or amidation, or any other method known in the art of peptide chemistry.
  • stereoisomer as it relates to a given compound is well understood in the art, and refers to another compound having the same molecular formula, wherein the atoms making up the other compound differ in the way they are oriented in space, but wherein the atoms in the other compound are like the atoms in the given compound with respect to which atoms are joined to which other atoms (e.g., an enantiomer, a diastereomer, or a geometric isomer).
  • hydrophilicity is used in the common manner of the field as having an affinity for water; readily absorbing and/or dissolving in water.
  • lipophilicity is used in the common manner of the field as having an affinity for, tending to combine with, or capable of dissolving in lipids.
  • amphipathicity describes a structure having discrete hydrophobic and hydrophilic regions. Thus, one portion of the structure interacts favorably with aqueous and other polar media, while another portion of the structure interacts favorably with non-polar media.
  • solubility describes the maximum amount of solute that will dissolve in a given amount of solvent at a specified temperature.
  • bioavailability refers to the systemic availability (i.e., blood/plasma levels) of a given amount of compound administered to a subject. The term further encompasses the rate and extent of absorption of compound that reaches the site of action.
  • the presently disclosed subject matter provides compounds having binding and/or modulation specificity for the TrkB receptor molecule.
  • the compounds are mimetics of a neurotrophin /Mum loop.
  • the neurotrophin is BDNF.
  • the /Murn loop is loop 2 of BDNF.
  • These compounds can be used in accordance with the presently disclosed pharmaceutical compounds and methods in the treatment and prevention of disorders, including but not limited to neurological disorders (e.g., neurodegenerative disorders).
  • Some TrkB binding and/or modulation compounds demonstrate agonist function and thus promote TrkB activation.
  • Some TrkB binding and/or modulation compounds demonstrate partial agonist function.
  • TrkB binding and/or modulation compounds can be isolated from natural sources, purchased from commercial sources, or synthesized or partially synthesized by methodology known in the art of synthetic organic chemistry, including parallel and combinatorial synthetic techniques.
  • NA Structure
  • a representative compound or mimetic of BDNF y?-tum loop 2 having binding and/or modulation specificity for a TrkB receptor molecule can comprise a compound having a structure of one of Formulas (I-XI).
  • the loop 2 BDNF mimetic compound has a structure of Formula (I):
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
  • Xi and X2 are independently selected from CH 2 and NR 4 , wherein R 4 is selected from H, alkyl, aralkyl, and aryl; and
  • Di is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
  • R 5 and Re are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt.
  • R-i, R 2 , and R 3 are H, Xi and X 2 are NH, and Di is alkoxy.
  • the compound of Formula (I) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (II):
  • L 1 and L 3 are independently selected from the group consisting of C 1 -C 5 alkylene, arylene, aralkylene, and substituted arylene;
  • L 2 is selected from the group consisting of C 1 -C 5 alkylene, arylene, aralkylene, substituted arylene,
  • L 4 is C1-C5 alkylene
  • Zi, Z 2 , and Z3 are independently selected from the group consisting of H, alkyl, aryl, and aralkyl;
  • X 3 , X 4 , X5, and X 6 are independently N or CH;
  • Y 1 , Y 2 , and Y 3 are independently carbonyl, sulfonyi, or methylene;
  • D 2 , D 3 , D 4 , and D 5 are independently selected from H, alkyl, halo, hydroxyl, mercapto, mercaptoalkyl, alkoxyl, aryloxyl, aralkoxyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dtalkylcarbamoyl,
  • R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • Li and L 3 are C 1 -C 5 alkylene or phenylene.
  • D 2 and D 3 are hydroxyl or carbamoyl.
  • X 3 and X 4 are N.
  • the compound of Formula (II) is selected from the group consisting of:
  • the loop 2 BDNF mimetic compound has a structure of Formula (III):
  • L 5 is present of absent, and when presne is d-Cs alkylene
  • X 7 and Xs are independently N or CH;
  • R-io and Rn are independently selected from the group consisting of H, halo, alkyl, and cyano;
  • D 6 , D 7 , and D 8 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 6 , R 7 , Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • R-io and Rn are cyano.
  • D 6 is hydroxyl.
  • D 7 is NR 5 R 6 .
  • D 8 is acylamino.
  • the compound of Formula (III) is
  • the loop 2 BDNF mimetic has a structure of Formula (IV):
  • X 9 and X 10 are independently CH 2 or NR 4 , wherein R 4 is selected from H, alkyl, aralkyl and aryl;
  • R 12 is selected from the group consisting of H, alkyl, aralkyl, aryl, acyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
  • R 13 is selected from H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkycarbamoyl, and dialkylcarbamoyl;
  • R 14 and R 1 S are independently selected from H alkyl, substituted alkyl, and aralkyl;
  • R 16 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and wherein R 5 and R 6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt thereof.
  • Ri 2 , R13, Ru, and R15 are H or alkyl.
  • X 9 and X 10 are NR 4 .
  • Ri 6 is NR 5 R 6 , wherein R 5 and R 6 are H or alkyl.
  • the compound of Formula (IV) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (V):
  • L 6 and L 7 are independently present or absent, and when present are CrC 5 alkylene;
  • X 11 is O, S, CH2 or NR 17 , wherein R 1 7 is selected from H, alkyl, aralkyl and aryl;
  • X12, X-I3, and Xi 4 are independently CH or N;
  • Xi 5 is selected, from the group consisting of O, S, and NRi 8 , wherein R 18 is selected from H, alkyl, aralkyl, and aryl; and
  • D 9 , D 10 , D 11 , and D 12 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • RQ, R ⁇ , Re, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • D 9 , Di 0 , Dn, and D 12 are hydroxyl, alkoxyl or carbamoyl.
  • the compound of Formula (V) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (Vl):
  • Le is present or absent, and when present is C 1 -C 5 alkylene;
  • X16 is selected from the group consisting of O, S, and NR19, wherein R-ig is selected from H, alkyl, aralkyl and aryl;
  • X 17 is selected from the group consisting of O, S, CH 2 , and NR 2 O, wherein R 2 o is selected from H, alkyl, aralkyl, and aryl;
  • Xi 8 and Xi 9 are independently selected from N and CH;
  • D-13 and Du are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , R 6 , R7, Re, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • D 13 and D 14 are hydroxyl, alkoxyl, or NR 5 R 6 , wherein R 5 and R 6 are H or alkyl.
  • the compound of Formula (Vl) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (VII): wherein: m and n are independently 1 or 2; each Lg and l_io can be present or absent, and when present is Ci-C 5 alkylene;
  • X 20 and X 21 are independently selected from CH, CH 2 , N, and NR 4 , wherein R 4 is selected from H, alkyl, aralkyl and aryl;
  • X22 is selected from H and halo; and each D 15 and each D-i ⁇ are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , Re, Rz, Re, and R 9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • X 22 is halo. In some embodiments, each Di 5 and each Di 6 are hydroxyl. In some embodiments, the compound of Formula (VII) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (VIII):
  • l_ii is present or absent, and when present is C- 1 -C 5 alkylene;
  • X 23 is N or CH
  • R21 and R22 are independently selected from the group consisting of H, alky], aralkyl, aryl and halo;
  • Di7, Die, and D 19 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, wherein Rs, Re, R 7 , Rs, and Rg are independently selected from H, alky], aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • R 2 i and R 2 2 are alkyl.
  • Di 7 , Die, and Di 9 are selected from hydroxyl, alkoxyl, and carbamoyl.
  • the compound of Formula (VIII) is selected from the group consisting of:
  • the loop 2 BDNF mimetic compound has a structure of Formula (IX): wherein:
  • L 12 is present or absent, and when present is Ci-C 5 alkylene
  • X 24 is N or CH
  • R 23 is selected from the group consisting of H, alkyl, aralkyl, aryl, and halo;
  • D 2 O, D 2 i, D 22 , D 23 , and D 23 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R 5 , R 6 , R 7 , Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • D 20 , D 2 i, D 22 , D 23 , and D 24 are selected from hydroxyl, alkoxyl, halo, and carbamoyl.
  • R 23 is alkyl.
  • the compound of Formula (IX) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (X):
  • t is 1 or 2; each L- I3 is present or absent, and when present is C 1 -C 5 alkylene;
  • X25 and X 26 are selected from N and CH;
  • X27 is selected from N, CH, CH 2 , and NR25, wherein R25 is H or alkyl;
  • R2 4 is selected from H, alkyl, aralkyl, aryl, and halo;
  • D25 and each D 2 6 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • D25 and each D 2 ⁇ are selected from hydroxyl and alkoxyl.
  • R 24 is alkyl.
  • the compound of Formula (X) is
  • the loop 2 BDNF mimetic compound has a structure of Formula (Xl):
  • X 2 8 is selected from CH 2 , O, S, and NR26, wherein R 2 6 is selected from H, alkyl, aralkyl, and aryl;
  • X 29 is N or CH
  • X30 is CH 2 or NR 27 ; wherein R2 7 is selected from H, alkyl, aralkyl, and aryl;
  • X 31 is N or CH
  • D 27 , D 28 , and D 2 g are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
  • R5, Re, R7, Rs, and Rg are independently selected from H 1 alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
  • D 27 , D 2 8, and D 2 9 are independently hydroxy! or alkoxyl.
  • the compound of Formula (Xl) is
  • the compounds disclosed herein can also encompass derivatives of a parent compound, which has binding and/or modulation specificity for a TrkB receptor molecule, wherein the derivative also has binding and/or modulation specificity for the TrkB receptor.
  • the derivative can exhibit enhancement in at least one of the characteristics selected from the group consisting of hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound.
  • the compound is a derivative of a parent compound having binding and/or modulation specificity for a TrkB receptor molecule, wherein the derivative is transformed in vivo to the parent compound or to another derivative of the parent compound that also has binding and/or modulation specificity for the TrkB receptor.
  • Such derivatives can be referred to in some embodiments as prodrugs.
  • Prodrugs can contain bonds that hydrolyze in vivo chemically (i.e., hydrolysis catalyzed by changes in pH) or enzymatically. Such bonds include, but are not limited to, esters, amides, and carbonates. Hydrolysis of such a bond in vivo can reveal, for example, a hydrogen donor moeity, such as an alcohol or an amine.
  • the compounds disclosed herein can encompass a pharmacophore substantially identical to the pharmacophore illustrated in Figure 1.
  • Representative such compounds include, but are not limited to, compounds encompassed by Formulae (I-XI). II.B. Formulations
  • the compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.
  • formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients to control the release of active compounds.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer.
  • the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
  • the compound can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • Formulations of the compounds can contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the formulations comprising the compound can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the compounds can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrollidone, sodium saccharine, cellulose, magnesium carbonate, etc.
  • compositions comprising the compounds of the presently disclosed subject matter can include an agent which controls release of the compound, thereby providing a timed or sustained release compound.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents suitable for use in the presently disclosed subject matter include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers suitable for use in the presently disclosed subject matter include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • Liquid carriers suitable for use in the presently disclosed subject matter can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • Liquid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
  • the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Solid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active compound.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Parenteral carriers suitable for use in the presently disclosed subject matter include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Carriers suitable for use in the presently disclosed subject matter can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • the carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art. II.D. Salts
  • the disclosed compounds can further comprise pharmaceutically acceptable salts.
  • Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluene
  • Base addition salts include but are not limited to, ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N, N 1 - dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl)- aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g. , lysine and arginine dicyclohexylamine and the like.
  • metal salts examples include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. 11.E. Tracers
  • the BDNF mimetic comprises a tracer or label that can be detected in vivo (i.e., in a living subject) or in vitro (i.e., outside a living subject).
  • the tracer is detectable in vivo by a non-invasive method, including, but not limited to, scintigraphic methods, magnetic resonance imaging, ultrasound, or fluorescence.
  • the tracer can be conjugated or otherwise associated with a BDNF mimetic, a drug carrier, or combinations thereof.
  • the biodistribution of the composition can be visualized.
  • a BDNF mimetic labeled with a radioactive tracer can be used to detect tumors or other pathological states with altered TrkB expression in vivo.
  • the label is detectable by a scintigraphic imaging method.
  • Scintigraphic imaging methods include SPECT (Single Photon Emission Computed Tomography), PET (Positron Emission Tomography), gamma camera imaging, and rectilinear scanning.
  • a gamma camera and a rectilinear scanner each represent instruments that detect radioactivity in a single plane.
  • Most SPECT systems are based on the use of one or more gamma cameras that are rotated about the subject of analysis, and thus integrate radioactivity in more than one dimension.
  • PET systems comprise an array of detectors in a ring that also detect radioactivity in multiple dimensions.
  • the detectable tracer or label can comprise a radionuclide label selected from the group consisting of, but not limited to, 18 fluorine, 64 copper, 65 copper, 67 gallium, 68 gallium, 77 bromine, 80m bromine, 95 ruthenium, 97 ruthenium, 103 ruthenium, 105 ruthenium, "technetium, 107 mercury, 203 mercury, 123 iodine/ 124 iodine, 125 iodine, 126 iodine, 131 iodine, 133 iodine, 111 indium, 113 mindium, 99m rhenium, 105 rhenium, 101 rhenium, 186 rhenium, 188 rhenium, 121 mtellurium, 122m tellurium, 125m tellurium, 165 thulium, 167 thulium, 168 thulium, and nitride or oxide forms
  • BDNF mimetic can be derivatized so that a radionuclide can be bound directly to it.
  • the radionuclide can take the place of a hydrogen atom of one of the BDNF mimetics described herein in Formulas (I-XI).
  • the radionuclide or radioactive tracer can be bound to a BDNF mimetic of Formulas (I-XI) through a suitable organic tether moiety, such as an alkylene group.
  • compositions comprising radionuclides When compositions comprising radionuclides are used, stabilizers to prevent or minimize radiolytic damage, such as ascorbic acid, gentisic acid, or other appropriate antioxidants, can be added to the composition comprising the labeled targeting molecule.
  • the presently disclosed subject matter provides novel methods of treating disorders, including, but not limited to, neurological disorders (e.g., neurodegenerative disorders) and in a subject. More particularly, the methods of the presently disclosed subject matter involve the administration of a compound having binding and/or modulation specificity for a TrkB receptor molecule in a subject to treat a disorder.
  • the compound can be administered in an amount effective to induce survival signaling and/or to upregulate neural function.
  • the compound can also be used to stimulate desired mechanisms of non-neural cells.
  • the compound can also be used to partially or fully block endogenous BDNF.
  • the disorder to be treated can be any condition that is mediated, at least in part, by binding of neurotrophins to the TrkB receptor, and conditions wherein the TrkB receptor is present, though not necessarily causally linked to the condition.
  • Neurotrophins can be present or absent in the condition.
  • Such disorders include, but are not limited to, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications, multiple sclerosis, peripheral nerve injury, conditions involving degeneration or dysfunction of cells expressing TYkB.
  • the disorder to be treated further includes depression, obesity, and ischemic conditions of peripheral tissues. Table 1 lists a variety of disorders to which TrkB involvement has been linked.
  • the presently disclosed subject matter further provides for methods of facilitating cell survival or function, including both neural cells and non-neural cells.
  • Representative neural cells include, but are not limited to, hippocampal pyramidal cells, cortical cells, striatal cells, substantial nigra cells, motor neuron cells, Purkinje cells, dorsal root ganglia cells.
  • Non- neuronal cells include, but are not limited to, vascular endothelial cells.
  • the methods can comprise treating a neural or non-neural cell with a compound having binding or modulation specificity for a TrkB receptor molecule, whereby the compound induces survival signaling and/or upregulation of cell function.
  • the BDNF mimetics of Formulas (I-XI) can be used in both in vivo and in vitro settings.
  • the BDNF mimetics can be used as a cost saving alternative to BDNF in in vitro methods.
  • the BDNF mimetics can be used in methods related to stem cells.
  • the BDNF mimetics can be used for maintaining stem cells in an undifferentiated state or to induce stem cell differentiation.
  • a BDNF mimetic as disclosed herein can be used in methods currently available in the art that employ BDNF (Huang, E.J., Reichardt LF.
  • the presently disclosed subject matter provides methods of administering compounds having binding and/or modulation specificity for a TrkB receptor compound in order to ameliorate a disorder mediated by TrkB binding or modulation in a subject.
  • the method can comprise administering to a subject an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor, such as any of the compounds disclosed herein.
  • administering can be effected or performed using any of the various methods known to those skilled in the art.
  • the compound can be administered, for example, subcutaneously, intravenously, parenterally, intraperitoneally, intradermal ⁇ , intramuscularly, topically, enteral (e.g., orally), rectally, nasally, buccaily, sublingually, vaginally, by inhalation spray, by drug pump or via an implanted reservoir in dosage formulations containing conventional non-toxic, physiologically acceptable carriers or vehicles.
  • the presently disclosed compounds can be administered to a localized area in need of treatment. This can be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, transdermal patches, by injection, by catheter, by suppository, or by implant (the implant can optionally be of a porous, non-porous, or gelatinous material), including membranes, such as sialastic membranes or fibers.
  • the form in which the compound is administered (e.g., syrup, elixir, capsule, tablet, solution, foams, emulsion, gel, sol) will depend in part on the route by which it is administered.
  • mucosal e.g., oral mucosa, rectal, intestinal mucosa, bronchial mucosa
  • nose drops, aerosols, inhalants, nebulizers, eye drops or suppositories can be used.
  • the compounds and agents disclosed herein can be administered together with other biologically active agents, such as analgesics, anti- inflammatory agents, anesthetics and other agents which can control one or more symptoms or causes of a TrkB mediated disorder.
  • administration can comprise administering to the subject a plurality of dosages over a suitable period of time.
  • administration regimens can be determined according to routine methods, upon a review of the instant disclosure.
  • administration comprises administering to the subject a dose or plurality of dosages to achieve a compound concentration in a cell or in a cell microenvironment of between about 0.10 ⁇ M and about 50 ⁇ M.
  • the compounds of the presently disclosed subject matter can be employed as the sole active agent in a pharmaceutical or can be used in combination (e.g., administered proximate in time to each other or even in the same formulation) with other active ingredients, e.g., neurotrophins, or other factors or drugs which can facilitate neural survival or axonal growth in neurodegenerative diseases.
  • other active ingredients e.g., neurotrophins, or other factors or drugs which can facilitate neural survival or axonal growth in neurodegenerative diseases.
  • synergistic effects can be provided by administering a compound having binding and/or modulation specificity for a TrkB receptor molecule to a subject with a second compound having binding and/or modulation specificity for a p75 NTR receptor molecule.
  • Representative compounds having binding specificity for p75 NTR receptor molecules are disclosed in U.S. Patent Application Serial No.
  • the compounds disclosed herein can take the form of a mimetic or fragment thereof, it is to be appreciated that the potency, and therefore dosage of an effective amount can vary. However, one skilled in the art can readily assess the potency of a compound of the type presently envisioned by the presently disclosed subject matter.
  • the compounds disclosed herein can be used in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art, or example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980). It will be appreciated by one of skill in the art that dosage range will be described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980). It will be appreciated by one of skill in the art that dosage range will be described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980). It will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated by one of skill in the art that dosage range will be appreciated
  • the dosage range is understood to be large enough to produce the desired effect in which the neurological disorder and the symptoms associated therewith are ameliorated and/or survival of the neural cells is achieved, but not be so large as to cause unmanageable adverse side effects.
  • the appropriate range for therapeutic effectiveness will be readily determined by one skilled in the art depending on the route of administration, age, and condition of the subject being treated.
  • the dosage can also be adjusted by the individual physician in the event of any complication. No unacceptable toxicological effects are expected when compounds disclosed herein are used in accordance with the presently disclosed subject matter.
  • an effective amount of the compounds disclosed herein comprise amounts sufficient to produce a measurable biological response.
  • Actual dosage levels of active ingredients in a therapeutic compound of the presently disclosed subject matter can be varied so as to administer an amount of the active compound that is effective to achieve the desired therapeutic response for a particular subject and/or application.
  • a minimal dose is administered, and the dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of a therapeutically effective dose, as well as evaluation of when and how to make such adjustments, are known to those of ordinary skill in the art.
  • a preferred subject is a vertebrate subject.
  • a preferred vertebrate is warm-blooded; a preferred warm-blooded vertebrate is a mammal.
  • the subject treated by the presently disclosed methods is desirably a human, although it is to be understood that the principles of the presently disclosed subject matter indicate effectiveness with respect to all vertebrate species which are to included in the term "subject.”
  • a vertebrate is understood to be any vertebrate species in which treatment of a neurodegenerative disorder is desirable.
  • the term "subject” includes both human and animal subjects.
  • veterinary therapeutic uses are provided in accordance with the presently disclosed subject matter.
  • the presently disclosed subject matter provides for the treatment of mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and/or animals of social importance to humans, such as animals kept as pets or in zoos.
  • mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and/or animals of social importance to humans, such as animals kept as pets or in zoos.
  • animals include but are not limited to: carnivores such as cats and dogs; swine, including pigs, hogs, and wild boars; ruminants and/or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; and horses.
  • domesticated fowl i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like
  • livestock including, but not limited to, domesticated swine, ruminants, ungulates, horses (including race horses), poultry, and the like.
  • the compounds of the presently disclosed subject matter can be used in coatings.
  • the BDNF mimetics of Formulas (I-XI) can be used to coat medical devices, such as surgical tools, biosensors, and implants, to promote neural and/or non-neural cell survival in tissues or fluids coming into contact with the medical device or to treat a pathological state with altered TrkB expression in an area in contact with the medical device.
  • the medical device is a cochlear implant, an electronic device interfacing with the nervous system, or a synthetic matrix designed to support neural regeneration.
  • the mimetics can be coated onto the medical devices by a variety of methods.
  • the mimetics can be suspended or dissolved in a liquid carrier, coated and dried onto the medical device.
  • the mimetics can be conjugated to a chemically funtionalized surface of a device or imbedded in or conjugated to a polymeric coating of a medical device.
  • the device being coated can have a metallic surface, such as, for example, stainless steel, nickel, titanium, aluminum, copper, gold, silver, platium, and combinations thereof.
  • the device can have a glass or polymeric surface.
  • Monoclonal anti-phospho-ERK T202/Y204 , polyclonal anti-ERK42/44, monoclonal anti-phospho-AKT s473 , polyclonal anti-AKT, polyclonal anti- phospho-NF/cB-p65(Ser 563 ), and site-specific polyclonal anti-Trk Y490 were obtained from Cell Signaling Technology, Inc. (Beverly, Massachusetts, United States of America). Monoclonal anti-actin was obtained from Sigma- Aldrich Corp. (St. Louis, Missouri, United States of America). Polyclonal TrkA and TrkB antibodies were obtained from Upstate USA, Inc. (Charlottesville, Virginia, United States of America). Recombinant human NGF was obtained from Invitrogen (Carlsbad, California, United States of America) and BDNF from Sigma-Aldrich (St. Louis, Missouri, United States of America).
  • Hippocampal neurons were prepared from E16-17 mouse embryos as previously described (Yang, T. et a/. (2003) J Neurosci 23, 3353-3363). Low density cultures were initiated in poly-L-lysine coated A/2 plates by adding 25 ⁇ of cell suspension (2000 neurons/well; 12,500 cells/cm 2 ), 25 ⁇ of DMEM containing 10% FBS, and different concentrations of recombinant BDNF, NGF, or TrkB-binding compounds to each well.
  • LY294002, PD98059 obtained from EMD Biosciences/Calbiochem, San Diego, California, United States of America
  • PD98059 obtained from EMD Biosciences/Calbiochem, San Diego, California, United States of America
  • hippocampal neurons derived from E16-17 mice were cultured in poly-L-lysine coated six-well plates (Corning, Inc., Corning, New York, United States of America) in DMEM containing 10% FBS, followed by incubation in serum-free DMEM for 2 hours before addition of neurotrophins or compounds.
  • neurons were harvested in lysis buffer consisting of: 20 mM Tris, pH 8.0, 137 mM NaCI, 1 % lgepal CA-630, 10% glycerol, 1 mM PMSF, 10 ⁇ g/ml aprotinin, 1 ⁇ g/ml leupeptin, 500 ⁇ M orthovanadate (Zhou, J., Valletta, J.S., Grimes, M. L., Mobley, W.C. (1995) J Neurochem 65, 1146-1156). Lysates were centrifuged, the supernatant collected, and protein concentrations determined using the BCA Protein Assay Reagent obtained from Pierce (Rockford, Illinois, United States of America). Western blots were performed as described previously (Yang, T. et al.
  • Compound 4 is predicted to have the most "drug-like" character by the Lipinski criteria (Lipinski, CA. (2000) J Pharm Toxicol Methods 44, 235-249) and blood- brain barrier calculations (Fu, X.C., Chen, CX, Liang, W.Q., Yu, Q. S. (2001 ) Acta Pharmacol Sin 22, 663-668; Clark, D. E. (2002) J Pharm Sci 88, 815- 821 ). As such, Compound 4 was selected for more detailed mechanistic study.
  • the top two panels in Figure 5A show that in NIH3T3 cells expressing TrkB, both BDNF and Compound 4 (BD2-4) activate TrkB as evidenced by Trk phosphorylation (indicated by probing with anti-Trk Y490 antibodies in the uppermost panel). Culture medium alone (CM) or treatment with NGF does not activate TrkB.
  • the second panel from the top shows the Western blot with anti-TrkB antibodies indicating the total amount of TrkB present.
  • NIH3T3 cells expressing TrkA were used. NGF promotes activation of TrkA as evidenced by Trk phosphorylation, but BDNF and Compound 4 do not.
  • NIH3T3 cells expressing TrkC were used.
  • the bottom panel indicates the total amount of TrkC present by probing with anti-TrkC antibodies.
  • NT-3 promotes the phosphorylation of Trk (upper panel), while culture medium alone (CM), BDNF, and Compound 4 do not.
  • quinolinic acid at 7.5 mM leads to death of approximately 50% of mouse E16 striatal neurons comparing culture medium alone (CM) to quinolinic acid in the absence of BDNF, over a dose range of 0 to 1.5 ng/mL, and BD2-4, over a dose range of 10-1000 nM, demonstrate similar efficacies in decreasing quinolinic acid-induced death.
  • the K252a inhibitor is a well-characterized inhibitor of TrkB receptor activation.
  • K252a had no effect on quinolinic acid- induced death but did block the ability of BDNF and BD2-4 to prevent death.
  • DARP32-positive neurons represent the population within the striatum that are particularly vulnerable in HD.
  • BD2-4 protects DARP32 — positive neurons with an efficacy similar to that of BDNF.
  • Figure 6C further demonstrates that this protection is mediated through TrkB and that the efficacy of BD2-4 is similar to that of BDNF.
  • the addition of the inhibitor K252a decreased the ability of BDNF and BD2-4 to prevent cell death ( Figure 6C).
  • human SH-SY5Y cells were used after terminal differentiation into a dopaminergic phenotype (Presqraves, S. P., et a/. (2004) Exp Neruol 190, 157-170).
  • Human SH- SY5Y neuroblastoma cells were propagated to confluence in Dulbecco's Modified Eagle's media (DMEM) supplemented with 10% fetal calf serum, 100 ⁇ g/mL penicillin, 100 ⁇ g/ml_ streptomycin, 0.25 ⁇ g/ml_ amphotericin B, and 0.01 ⁇ M non-essential amino acids and then sub-cultured for differentiation.
  • DMEM Dulbecco's Modified Eagle's media
  • the cells were incubated in same media containing 10 ⁇ M retinoic acid for 3 days; then the media was removed and replaced with media containing 160 nM of the phorbol ester 12-0- tetradecanoyl-phorbol-13-acetate (TPA) for 3 days of differentiation.
  • TPA phorbol ester 12-0- tetradecanoyl-phorbol-13-acetate
  • the cells were then administered a range dose of BD2-4 or BDNF (1 x10 '12 M to 1 mM) in DMEM for 30 mins for three days prior to addition of 100 ⁇ M MPP + .
  • TrkB inhibitor K252a 200 nM
  • MPP + promotes death of essentially all cells.
  • the death-inducing activity of MPP + is significantly blocked to a similar extent by both BDNF and BD2-4.
  • K252a blocks a significant amount of the protection afforded by BDNF and BD2-4, indicating that this protective effect is mediated through the activation of TrkB.
  • Mean + SE are shown.
  • NGF mimetic LM11A-31 known to act as a ligand at the NGF p75 NTR receptor (described in U. S. Patent Application Serial No. 11/396,936, filed April 3, 2006), blocked A/?-induced degeneration. This blocking activity was itself blocked by NGF, consistent with NGF competing with LM11A-31 at the p75 NTR receptor and thereby inhibiting its protective effect.
  • BDNF mimetics BD2-4 (Compound 4) and BD2-24 (Compound 24) were as effective as BDNF in blocking A/?-induced degeneration. These studies demonstrate for the first time that BDNF can block A ⁇ oligomer- induced degeneration and that BDNF mimetics are equally as effective in blocking the A/? oligomer-induced degeneration as BDNF protein.

Abstract

Methods and compounds for treating neurological and other disorders are provided. Included is the administering to a subject in need thereof an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor molecule.

Description

DESCRIPTION
METHODS OF FACILITATING NEURAL CELL SURVIVAL USING NON-PEPTIDE AND PEPTIDE BDNF NEUROTROPHIN MIMETICS
CROSS REFERENCE TO RELATED APPLICATIONS
This application is based on and claims priority to United States Provisional Application Serial Number 60/688,767, filed June 8, 2005, herein incorporated by reference in its entirety.
GRANT STATEMENT
The presently disclosed subject matter was made with U.S. Government support under Grant No. NS30687 awarded by the National Institutes of Health and Grant No. 40967 awarded by The Institute on Aging. As such, the U.S. Government has certain rights in the presently disclosed subject matter.
TECHNICAL FIELD
The presently disclosed subject matter generally relates to the treatment of disorders in a subject, including but not limited to neurological disorders. More particularly, the methods of the presently disclosed subject matter relate to administering to a subject an effective amount of a compound having binding and/or modulation specificity for the TrkB receptor molecule to treat a disorder in the subject.
TABLE OF ABBREVIATIONS
2D two-dimensional
3D three-dimensional
A/? amyloid-/?
Ab antibody
AD Alzheimer's disease
ALS amyotrophic lateral sclerosis
BCA bicinchoninic acid BDNF brain-derived neurotrophic factor b.i.d. twice daily cm centimeter d day
D Dalton
DMEM Dulbecco's Modified Eagle Media
ECL electrogenerated chemiluminescence
EDTA ethylenediamine tetraacetic acid
ELISA Enzyme Linked Immunosorbent Assay
ERK extracellular signal-regulated protein kinase
FBS fetal bovine serum g gram h hour
HBA hydrogen bond acceptor
HBD hydrogen bond donor
HD Huntington's disease
HEPES 4-2-hydroxyethyl-1-piperazineethanesulfonic acid
HRP horseradish peroxidase
IgG lmmunoglobin G
IP Intraperitoneal
IV intravenous
K32 lysine residue number 32 kcal kilocalorie kg kilogram
MBP myelin basic protein mg milligram min minute ml milliliter mM millimolar mol mole
MTT 3-(4,5-dimethylthiazol-2-yl)-2,
5-diphenyltetrazolium bromide MW molecular weight
NaC! sodium chloride ng nanogram nM nanomolar
NS not significant
NMR nuclear magnetic resonance
NGF nerve growth factor nM nanomolar
P probability p75NTR p75 neurotrophin receptor
PBS phosphate-buffered saline
PD Parkinson's disease pmol picomole
PMSF phenylmethylsulfonyl fluoride
PO per os (by mouth) pro-NGF unprocessed precursor of NGF
PVDF Polyvinylidine Difluroide
SDS sodium dodecyl sulfate
SE standard error s.e.m. standard error of measurement
Tris 2-Amino-2-(hydroxymethy!)-1 ,3-propanediol
TUNEL Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling
/JQ microgram μ\ microliter μM micromolar
% percent
0C degrees Celsius
> greater than or equal to
> greater than
< less than or equal to
< less than BACKGROUND
Neurotrophins are polypeptides that play a role in the development, function, and/or survival of certain cells, including neurons. The death or dysfunction of neurons has been directly implicated in a number of neurological disorders. It has been suggested that alterations in neurotrophin localization, expression levels of neurotrophins, and/or expression levels of the receptors that bind neurotrophins are linked to neuronal degeneration or dysfunction. This degeneration or dysfunction can occur in the neurological disorders Alzheimer's, Parkinson's, Huntington's disease and amyotrophic lateral sclerosis (ALS), among others. Neurotrophins also mediate fundamental mechanisms relevant to non- neurological disorders including for example depression, obesity, and ischemic conditions of peripheral tissues.
A variety of neurotrophins have been identified, including Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5), Neurotrophin 6 (NT-6) and Brain Derived Neurotrophic Factor (BDNF). Neurotrophins are found in both precursor form, known as pro- neurotrophins, and in mature form. The mature forms are proteins of about 120 amino acids in length that exist in physiological states as stable, non- covalent approximately 25 kDa homodimers. Each neurotrophin monomer includes three solvent-exposed ^-hairpin loops, referred to as loops 1 , 2, and 4 that exhibit relatively high degrees of amino acid conservation across the neurotrophin family.
Mature neurotrophins bind preferentially to the receptors Trk and p75NTR, while pro-neurotrophins, which contain an N-terminal domain proteolytically removed in mature forms, interact principally with the p75NTR receptor and through their N-terminal domains, with the sorting receptor sortilin (Fahnestock, M., Michalski, B., Xu, B., Couqhlin, M.D. (2001 ) MoI
Cell Nθurosci 18, 210-220; Harrington, A. VV. et al. (2004) Proc Natl Acad Sci USA 101 , 6226-6230; Nvkiaer, A. et al., (2004) Nature 427. 843-848). The p75NTR receptor interacts with Trks and modulates Trk signaling, but is also independently coupled to several signaling systems, including pro-survival signals, IRAK/TRAFΘ/NFΛ-B, PI3/AKT, and pro-apoptotic signals, NRAGE/JNK (Mamidipudi, V., Li. X., Wooten, M.W. (2002) J Biol Chem 277, 28010-28018; Roux, P.P.. Bhakar. A.L.. Kennedy. T.E.. Barker. P.A. (2001 ) J Biol Chem 276, 23097-23104; Salehi. A.H., et a/. (2000) Neuron 27, 279- 288).
Depending on the operative ligands, co-expression of Trk or other receptors, and expression of downstream signaling elements, p75NTR promotes cell survival or death. proNGF induces death of superior cervical ganglion neurons and oligodendrocytes through p75NTR, and its comitant binding to p75NTR and sortilin has been shown to activate cell death pathways (Nvkiaer. A. et al., (2004) Nature 427, 843-848; Lee. R., Kermani, P.. Teng. K.K., Hempstead, B.L (2001 ) Science 294, 1945-1948; Beattie. M.S., et al. (2002) Neuron 36, 375-386).
When administered for therapeutic use, neurotrophins exhibit suboptimal pharmacological properties, including poor stability with low serum half lives, likely poor oral bioavailability, and restricted central nervous system penetration (Podulso, J. F., Curran, G. L. (1996) Brain Res MoI Brain Res 36, 280-286; Saltzman, W.M., Mak, M.W., Mahonev, M.J., Duenas, E.T.. Cleland, J.L (1999) Pharm Res 16, 232-240; Partridge. W. M. (2002) Adv Exp Med Bio 513, 397-430). Additionally, the highly pleiotropic effects of neurotrophins achieved through action of the triple receptor signaling network increases the chances of adverse effects.
Unfortunately, technical and ethical considerations have thus far hampered the development of therapeutic agents based upon neurotrophins. For example, it is technically difficult to produce sufficient quantities of pure neurotrophins using recombinant DNA techniques. Additionally, although it is possible to utilize human fetal cells to produce neurotrophins, the ethical ramifications raised by the use of such cells (typically obtained from an aborted fetus) have all but prevented the utilization of this approach. Previous studies have described the creation of synthetic peptides corresponding to various domains of the BDNF protein that are capable of achieving the BDNF effect of promoting neurite outgrowth (O'Leary and Hughes, 2003; Williams et al., 2005; Fletcher and Hughes, 2006). While it is not known if these synthetic BDNF peptides actually activate the TrkB receptor or whether they achieve their neurotrophic effects by a non-TrkB mechanism, these peptides are too large (approximately 2000 MW) to constitute actual medicinal compounds.
Accordingly, there is an unmet need in the art for the development of small molecule (for example, < 500 MW, characteristic of successful drugs) non-peptidyl or peptide agents based upon neurotrophins for use in the treatment of disorders. In particular, there is a need to identify small molecules that mimic key regions of neurotrophin proteins and have the ability to activate the TrkB receptor. There is further a need for small molecules that target TrkB receptors to avoid or minimize potentially deleterious interactions with the p75NTR and sortilin receptors.
SUMMARY
This Summary lists several embodiments of the presently disclosed subject matter, and in many cases lists variations and permutations of these embodiments. This Summary is merely exemplary of the numerous and varied embodiments. Mention of one or more representative features of a given embodiment is likewise exemplary. Such an embodiment can typically exist with or without the feature(s) mentioned; likewise, those features can be applied to other embodiments of the presently disclosed subject matter, whether listed in this Summary or not. To avoid excessive repetition, this Summary does not list or suggest all possible combinations of such features. Disclosed herein are methods of treating a disorder in a subject, including both neurological and non-neurological disorders, comprising administering to the subject an effective amount of a small molecule compound having binding and/or modulation specificity for a TrkB receptor molecule. In some embodiments, the disorder is selected from the group consisting of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Rett syndrome, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications, motor neuron disease, multiple sclerosis, HIV dementia, peripheral nerve injury, hearing loss, depression, obesity, metabolic syndrome, pain, cancer, and conditions involving degeneration or dysfunction of cells expressing TrkB.
In some embodiments, the subject is a human subject.
Also disclosed herein are methods of facilitating neural cell survival or promoting neural function comprising treating a neural cell with a compound having the ability to specifically bind and/or modulate the activity of a TrkB receptor molecule.
Additionally disclosed herein are compounds having binding and/or modulation specificity for a TrkB receptor molecule.
In some embodiments, the compound having binding and/or modulation specificity for a TrkB receptor molecule is a mimetic of a BNDF /?-turn loop.
In some embodiments, the compound comprises a pharmacophore substantially identical to the pharmacophore illustrated in Figure 1.
In some embodiments, the compound is a small molecule or small peptide.
In some embodiments, the BNDF /?-tum loop is loop 2.
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (I):
Figure imgf000008_0001
wherein:
R-i, R2, and R3 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryioxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
X1 and X2 are independently selected from CH2 and NR4, wherein R4 is selected from H, alkyl, aralkyl, and aryl; and
Di is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000009_0001
, wherein R5 and R6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt.
In some embodiments, the compound of Formula (I) is
Figure imgf000009_0002
or a stereoisomer thereof.
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (II):
D2 L1-X3 Y1 L2 Y2 X4-L3 D3 /||\
I I
Z1 Z2 wherein:
L1 and L3 are independently selected from the group consisting of CrC5 alkylene, arylene, aralkylene, and substituted arylene;
L2 is selected from the group consisting of C1-C5 alkylene, arylene, aralkylene, substituted arylene,
Figure imgf000009_0003
L4 is C1-C5 alkylene;
Zi, Zz1 and Z3 are independently selected from the group consisting of H, alkyl, aryl, and aralkyl;
X3, X4, X5, and X6 are independently N or CH;
Yi, Y2, and Y3 are independently carbonyl, sulfonyl, or methylene; and
D2, D3, D4, and D5 are independently selected from H, alkyl, halo, hydroxy!, mercapto, mercaptoalkyl, alkoxyl, aryloxyl, aralkoxyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000010_0001
wherein R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (II) is selected from the group consisting of:
Figure imgf000010_0002
Figure imgf000010_0003
Figure imgf000011_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (III):
Figure imgf000011_0002
wherein: l_5 is present or absent, and when present is C-i-Csalkylene;
Xr and X8 are independently N or CH;
Rio and Rn are independently selected from the group consisting of H, halo, alky), and cyano;
D6, D7, and Da are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000011_0003
wherein R5, R6, Rj, Ra, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (III) is
Figure imgf000012_0001
In some embodiments, the loop 2 BDNF mimetic has a structure of Formula (IV):
Figure imgf000012_0002
wherein:
Xg and X10 are independently CH2 or NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
R-I2 is selected from the group consisting of H, alkyl, aralkyl, aryl, acyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
R-13 is selected from H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkycarbamoyl, and dialkylcarbamoyl;
Ru and R15 are independently selected from H alkyl, substituted alkyl, and aralkyl; and
Ri 6 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000012_0003
wherein R5 and R6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IV) is
Figure imgf000013_0001
or a stereoisomer thereof.
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (V):
Figure imgf000013_0002
wherein:
Le and L7 are independently present or absent, and if present are C-I-C5 alkylene;
Xii is O, S, CH2 or NR17, wherein Ri7 is selected from H, alkyl, aralkyl and aryl;
X12, Xi3, and X14 are independently CH or N; X-I5 is selected from the group consisting of O, S, and NR18, wherein R1S is selected from H, alkyl, aralkyl, and aryl; and
Dg, D1O, D11, and D12 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000013_0003
R5, RQ, R7, Rs, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V) is
Figure imgf000014_0001
or a stereoisomer thereof.
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (Vl):
Figure imgf000014_0002
wherein:
L8 is present or absent, and when present is C1-C5 alkylene; X-I6 is selected from the group consisting of O, S, and NRi9, wherein R19 is selected from H, alkyl, aralkyl and aryl;
X-I7 is selected from the group consisting of O, S, CH2, and NR20, wherein R20 is selected from H, alkyl, aralkyl, and aryl;
Xi8 and X19 are independently selected from N and CH; and D-13 and Du are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000014_0003
wherein R5, RQ, R7, RS, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (Vl) is
Figure imgf000015_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (VII):
Figure imgf000015_0002
wherein: m and n are independently 1 or 2; each Lg and L10 can be present or absent, and when present is C1-C5 alkylene;
X20 and X21 are independently selected from CH, CH2, N, and NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
X22 is selected from H and halo; and each Di5 and each Di6 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000016_0001
wherein R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (VII) is
Figure imgf000016_0002
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (VIII):
Figure imgf000016_0003
wherein:
Li1 is present or absent, and when present is C1-C5 alkylene; X23 is N or CH; F?2i and R22 are independently selected from the group consisting of H, alkyl, aralkyl, aryl and halo; and
D17, D18, and D19 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000017_0001
wherein Rs, R6, R7, Re, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (VIII) is selected from the group consisting of:
Figure imgf000017_0002
Figure imgf000018_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (IX):
Figure imgf000018_0002
wherein:
L12 is present or absent, and when present is CrC5 alkylene;
X24 is N or CH;
R23 is selected from the group consisting of H, alkyl, aralkyl, aryl, and halo; and
O20, D2-I, D22, D23, and D23 are independently selected from H1 alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyioxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000018_0003
wherein R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IX) is
Figure imgf000019_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (X):
Figure imgf000019_0002
wherein: t is 1 or 2; each L13 is present or absent, and when present is Ci-C5 alkylene;
X25 and X26 are selected from N and CH;
X27 is selected from N, CH, CH2, and NR25, wherein R25 is H or alkyl;
R24 is selected from H, alkyl, aralkyl, aryl, and halo; and
D25 and each D26 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000019_0003
wherein R5, Re, R7, Rs, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (X) is
Figure imgf000020_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (Xl):
Figure imgf000020_0002
wherein:
X28 is selected from CH2, O, S, and NR26, wherein R26 is selected from H, alkyl, aralkyl, and aryl;
X29 is N or CH;
X30 is CH2 or NR27; wherein R27 is selected from H, alkyl, aralkyl, and aryl;
X31 is N or CH; and
D27, D28, and D29 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000021_0001
wherein R5, Re, R7, Rs, and R9 are independently selected from H, alky), aralkyl, and aryl; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Xl) is
Figure imgf000021_0002
In some embodiments, the compound is a derivative of a parent compound having binding and/or modulation specificity for a TrkB receptor molecule, wherein the derivative also has binding and/or modulation specificity for the TrkB receptor or wherein the derivative is modified in vivo to form a compound having binding and/or modulation specificity for the TrkB receptor. In some embodiments, the derivative exhibits an enhancement in at least one of the characteristics selected from the group consisting of potency, selectivity, hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound.
An object of the presently disclosed subject matter is to provide methods of and compositions for facilitating neural cell survival or promoting the function of neurons or other TrkB-bearing cells using BDNF small molecule mimetics.
An object of the presently disclosed subject matter having been stated hereinabove, and which is addressed in whole or in part by the present presently disclosed subject matter, other objects will become evident as the description proceeds when taken in connection with the accompanying examples and drawings as best described hereinbelow.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a ribbon representation of the X-ray crystal structure of a portion of human BDNF peptide including loop 2. Hydrogen bonding features are represented by pairs of spheres with their relative positions indicating the locations of the acceptor and donor. One of the spheres of each pair is centered on putative acceptor/donor features in the model, while the other (i.e., the sphere centered on the pointed end of the arrow) indicates the target location of a complementary feature on any potentially interacting molecule. The diameter of the spheres represents a spatial tolerance for chemical feature matching in 3D conformer library scans.
Figure 2 is a series of fluorescence photomicrographs of E16 mouse hippocampal neuronal cultures treated with culture medium only (CM) or medium containing BDNF or Compound 4 (also referred to in the figures as
LM22A-4 and BD2-4), showing that Compound 4 has neurotrophic effects similar to that of BDNF. Neurons are immunostained with GAP43 antibody.
Figures 3A-3E are a series of neuron survival dose response curves of BDNF (Figure 3A), Compound 1 (also referred to as BD2-1 , Figure 3B) Compound 2 (also referred to as BD2-2, Figure 3C), Compound 3 (also referred to as BD2-3, Figure 3D), and Compound 4 (also referred to as BD2- 4, Figure 3E) using Mouse E16 hippocampal neurons. Survival was determined as the total number of cells in each well that were both morphologically intact and filled with blue formazan MTT conversion product (Lonqo, F. M., Manthorpe, M., Xie, Y.M., and Varon, S. (1997) J Neurosci Res. 48, 1-17). Counts were normalized to survival achieved with 25 ng/mL BDNF. Survival was assessed at 48 hrs. Symbols and bars indicate mean +/- s.e.m., and lines are fits of a single exponential rise model to the data. Figure 4 is a bar graph comparing neuron survival (Mouse E16 hippocampal neurons) with no treatment (CM), treatment with BDNF (50 ng/mL), with Compound 4 (BD2-4), or with a combination of BDNF and Compound 4 (BDNF + BD2-4), showing that Compound 4 is a partial agonist of BDNF. This is the first observation that a small moleucle BDNF mimetic can function as a partial agonist.
Figure 5A is a digital composite image of Western blots monitoring Trk activation as indicated by promotion of Trk phosphorylation at Y490 in NIH3T3 cells expressing either TrkB (upper two panels) or TrkA (lower two panels) demonstrating that BDNF and Compound 4 (BD2-4) (as indicated above each lane in the blots) activate TrkB and not TrkA while NGF (second column from left) activates TrkA but not TrkB. The upper lane for each pair shows staining with anti-p-TrkY490 antibody (p-TrkY490), while the lower lane of each pair shows total TrkB or TrkA. CM represents culture medium.
Figure 5B is a digital composite image of Western blots monitoring TrkC activation as indicated by promotion of Trk phosphorylation at Y490 in NIH3T3 cells expressing TrkC. BDNF and Compound 4 (BD2-4) (the right two lanes) do not activate TrkC, while NT-3 (second lane from the left) activates TrkC. CM represents culture medium.
Figure 6A is a bar graph showing prevention of quinolinic acid- induced death of mouse E16 striatal neurons by varying concentrations of BDNF and Compound 4 (BD2-4). The quinolinic acid-induced death is used as a model for neuronal death in Huntington's disease (HD). Application of quinolininc acid at 7.5 mM leads to death of approximately 50% of neurons as seen comparing culture medium alone (CM) to quinolinic acid in the absence of BDNF. Bars indicate mean ± s.e.m.
Figure 6B is a bar graph showing the effects of K252a (a TrkB receptor activation inhibitor) on the prevention of quinolinic acid-induced death in mouse E16 striatal neurons by BDNF and Compound 4 (BD2-4). CM represents culture medium and QUIN represents quinolinic acid. Bars indicate mean ± s.e.m and *** indicates p < 0.005 student t test.
Figure 6C is a bar graph of the results of a study similar to that described for Figure 6B only using Darp32-positive neurons. Bars indicate mean ± s.e.m and *** indicates p < 0.005 student t test. Figure 7 is a bar graph showing that BDNF mimetics prevent neuronal death in a Parkinson's disease (PD) model. As indicated by the bar second from the left, the TrkB inhibitor K252a has a small effect on lowering cell survival in the SH-SY5Y neuroblastoma cells compared to cells treated with culture medium (CM) alone. The neurotoxin 1-methyl-4-phenylpyridinium (MPP+, 100 μM) promotes death of essentially all cells. The death-inducing activity of MPP+ is significantly blocked to a similar extent by BDNF and BD2-4 (Compound 4). K252a blocks the protection effect of BDNF and BD2-4 (the two bars on the right of the graph) indicating that this protective effect is mediated through the activation of TrkB. Mean + SE are shown. One-Way ANOVA showed signficant effects between drug conditions (F = 648.2, P < 0.0001). *** P < 0.001 vs MPP+, # P < 0.001 vs CM.
Figure 8 is a bar graph showing that BDNF and BDNF mimetics prevent A/?-induced neuronal degeneration in E16-17 hippocampal neurons. Neuronal cell survival in culture medium (CM) and with the addition of 10 μM A/?scrambied oligomer are shown in the two bars on the left-hand side of the graph as positive controls. Cells were also treated with 10 μM A#i-42 alone or in combination with NGF (lOOng/mL), NGF mimetic LM11A-31 (100 nM), a combination of NGF and LM11A-31 , Compound 4 (BD2-4, 500 nM), Compound 24 (BD2-24, 500 nM), or either 20 or 100 ng/mL BDNF, as indicated under each bar. Addition of A/?i-42 oligomer but not control A/?scrambied oligomer resulted in an approximate 40% reduction in neuronal survival. BDNF mimetics BD2-4 and BD2-24 were as effective as BDNF in blocking A/?-induced degeneration. Mean + SE are shown and *** p < 0.001 for survival above CM baseline.
DETAILED DESCRIPTION
In subjects with particular disorders, including neurological and other disorders, alterations in neurotrophin localization, expression levels of neurotrophins, and/or expression levels of the receptors that bind neurotrophins can occur. Accordingly, by providing subjects suffering from such disorders with a corresponding neurotrophic factor or mimetic thereof, such neural degeneration can be alleviated or prevented. In some cases, inhibition of neurotrophin function would be of benefit. As disclosed for the first time herein, methods of treating a disorder and/or facilitating neural cell survival by administering a non-peptide compound having binding and/or modulation specificity for the TrkB receptor molecule are provided.
The methods and compounds of the presently disclosed subject matter relate to compounds having binding and/or modulation specificity for the TrkB receptor molecule. As used herein, discovery by in silico screening of compounds having binding and/or modulation specificity for the TrkB receptor are suitable for positively regulating survival or function of neural and other cells. Particularly, in cells showing trophic responses to neurotrophins, the compounds can promote survival signaling.
I Definitions It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Throughout the specification and claims, a given chemical formula or name shall encompass all optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods and materials are herein described.
Following long-standing patent law convention, the terms "a", "an", and "the" refer to "one or more" when used in this application, including the claims. Thus, for example, reference to "a carrier" includes mixtures of one or more carriers, two or more carriers, and the like. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter. The term "about", as used herein when referring to a measurable value such as an amount of weight, time, dose, etc. is meant to encompass in one example variations of ±20% or ±10%, in another example ±5%, in another example ±1%, and in yet another example ±0.1 % from the specified amount, as such variations are appropriate to perform the disclosed methods.
As used herein, the term "neurological disorder" includes any disorder characterized by damage of nervous system cells and include the following, without limitation, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications complications, multiple sclerosis, peripheral nerve injury, and conditions involving degeneration or dysfunction of cells expressing Trkb.
As used herein the term "alkyl" refers to Ci-2o inclusive, linear {i.e., "straight-chain"), branched, or cyclic (a "cycloalkyl"), saturated or at least partially and in some cases fully unsaturated {i.e., alkenyl and alkynyl) hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te/Y-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, methylpropynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups. "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having 1 to about 8 carbon atoms {i.e., a C-i-s alkyl), e.g., 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms. "Higher alkyl" refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" refers, in particular, to C-ι_8 straight-chain alkyls. In other embodiments, "alkyl" refers, in particular, to Ci-8 branched-chain alkyls.
Alkyl groups can optionally be substituted (a "substituted alkyl") with one or more alkyl group substituents, which can be the same or different. The term "alkyl group substituent" includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.
Thus, as used herein, the term "substituted alkyl" includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
Further, as used herein, the terms alkyl and/or "substituted alkyl" include an "allyl" or an "allylic group." The terms "allylic group" or "allyl" refer to the group -CH2HC=CH2 and derivatives thereof formed by substitution. Thus, the terms alkyl and/or substituted alkyl include allyl groups, such as but not limited to, allyl, methylallyl, di-methylallyl, and the like. The term "allylic position" or "allylic site" refers to the saturated carbon atom of an allylic group. Thus, a group, such as a hydroxyl group or other substituent group, attached at an allylic site can be referred to as "allylic."
The term "aryl" is used herein to refer to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety. The common linking group also can be a carbonyl, as in benzophenone, or oxygen, as in diphenylether, or nitrogen, as in diphenylamine. The term "aryl" specifically encompasses heterocyclic aromatic compounds. The aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others. In particular embodiments, the term "aryl" means a cyclic aromatic comprising about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings.
The aryl group can be optionally substituted (a "substituted aryl") with one or more aryl group substituents, which can be the same or different, wherein "aryl group substituent" includes alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and -NR1R", wherein R' and R" can each be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl. Thus, as used herein, the term "substituted aryl" includes aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto. Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, fluorene, and the like. A structure represented generally by a formula such as:
Figure imgf000028_0001
as used herein refers to a ring structure, for example, but not limited to a
3-carbon, a 4-carbon, a 5-carbon, a 6-carbon, and the like, aliphatic and/or aromatic cyclic compound comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and number of R groups is determined by the value of the integer n. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the structure:
Figure imgf000029_0001
wherein n is an integer from 0 to 2 comprises compound groups including, but not limited to:
.
Figure imgf000029_0002
and the like.
The structure:
Figure imgf000029_0003
wherein n is one (1 ) comprises compound groups including:
Figure imgf000029_0004
wherein the one (1 ) R substituent can be attached at any carbon on the benzofuran parent structure not occupied by another designated substituent, as in this case carbon 6 is substituted by X and carbon 2 is substituted by Y. A dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being "absent," the named atom is replaced by a direct bond. When the linking group or spacer group is defined as being absent, the linking group or spacer group is replaced by a direct bond. "Alkylene" refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally unsaturated and/or substituted with one or more "alkyl group substituents." There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl"), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6Hi0-); -CH=CH-CH=CH-; -CH=CH-CH2-; -(CH2)q- N(R)-(CH2)r-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-0-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons.
"Arylene" refers to a bivalent aryl group. An exemplary arylene is phenylene, which can have ring carbon atoms available for bonding in ortho, meta, or para positions with regard to each other, i.e.,
Figure imgf000030_0001
respectively. The arylene group can also be napthylene or a divalent fluorene moiety. The arylene group can be optionally substituted (a "substituted arylene") with one or more "aryl group substituents" as defined herein, which can be the same or different. "Aralkylene" refers to a bivalent group that contains both alkyl and aryl groups. For example, aralkylene groups can have two alkyl groups and an aryl group (i.e., -alkyl-aryl-alkyl-), one alkyl group and one aryl group (i.e., - alkyl-aryl-) or two aryl groups and one alkyl group (i.e., -aryl-alkyl-aryl-)
As used herein, the term "acyl" refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent (i.e., as represented by RCO — , wherein R is an alkyl, aralkyl, or aryl group as defined herein). As such, the term "acyl" specifically includes arylacyl groups, such as an acetylfuran and a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl. "Cyclic" and "cycloalkyl" refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can be optionally partially unsaturated. The cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Further, the cycloalkyl group can be optionally substituted with a linking group, such as an alkyiene group as defined hereinabove, for example, methylene, ethylene, propylene, and the like. In such cases, the cycloalkyl group can be referred to as, for example, cyclopropylmethyl, cyclobutylmethyl, and the like. Additionally, multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl. "Alkoxyl" or "alkoxy" refer to an alkyl-O- group wherein alkyl is as previously described. The term "alkoxyl" as used herein can refer to C1-20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo- hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, £-butoxyl, and pentoxyl.
"Aryloxyl" refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term "aryloxyl" as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl. "Aralkyl" refers to an aryl— alkyl— group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
The term "aralkoxyl" refers to an aralkyl-0 group wherein aralkyl is as described above. "Aralkyloxyl" refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl.
"Alkylamino" refers to an -NHR group wherein R is an alkyl group or substituted alkyl group as previously described.
"Dialkylamino" refers to an -NRR' group wherein each of R and R' is independently an alkyl group and/or a substituted alkyl group as previously described. Exemplary dialkylamino groups include ethylmethylamino, dimethylamino, and diethylamino.
"Alkoxycarbonyl" refers to an alkyl-O-CO- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and if-butyloxycarbonyl.
"Aryloxycarbonyl" refers to an aryl-O-CO- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
"Aralkoxycarbonyl" refers to an aralkyl-O-CO- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. "Carbamoyl" refers to an H2N-CO- group. "Alkylcarbamoyl" refers to a R1RN-CO- group wherein one of R and R1 is hydrogen and the other of R and R' is alkyl and/or substituted alkyl as previously described.
"Dialkylcarbamoyl" refers to a R1RN-CO- group wherein each of R and R1 is independently alkyl and/or substituted alkyl as previously described.
"Acyloxyl" refers to an acyl-O- group wherein acyl is as previously described.
"Acylamino" refers to an acyl-NH- group wherein acyl is as previously described.
The term "alkenylene" denotes an acyclic carbon chain (i.e., having an open-chain structure) having a carbon-to-carbon double bond and is represented by the formula CnH2n-2, which optionally can be substituted one or more times. Representative alkenylene groups include, but are not limited to, ethenylene, propenylene, 1- or 2-butenylene, 1-, or 2-pentylene, and the like.
"Aroylamino" refers to an aroyl-NH- group wherein aroyl is as previously described.
The term "amino" refers to the -NH2 group. The term "carbonyl" refers to the -(C=O)- group.
The term "carboxyl" refers to the -COOH group.
The term "cyano" refers to the -CN group.
The terms "halo", "halide", or "halogen" as used herein refer to fluoro, chloro, bromo, and iodo groups. The terms "hydroxyl" and "hydroxy" refer to the -OH group.
The term "hydroxyalkyl" refers to an alkyl group substituted with an - OH group.
The term "mercapto" refers to the -SH group.
The term "mercaptoalkyl refers to the -SR group wherein R is alkyl or substituted alkyl.
The term "oxo" refers to a compound described previously herein wherein a carbon atom is replaced by an oxygen atom. The term "nitro" refers to the -NO2 group.
The term "thio" refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
The term "sulfate" refers to the -SO4 group. The term "sulfonyl" refers to the -S(=O)2- group.
The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing one or more rings, for example, one ring, two rings, three rings, or four rings, with three or more carbon atoms per ring, for example, 3, 4, 5, 6, 7, or 8 carbon atoms per ring. Exemplary cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
The term "substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 , 2, 3, or 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
When the term "independently selected" is used, the substituents being referred to (e.g., R groups, such as groups Ri and R2, or groups X and Y), can be identical or different. For example, both Ri and R2 can be substituted alkyls, or Ri can be hydrogen and R2 can be a substituted alkyl, and the like.
A named "R," "X," "Y," "D," "L," or "2" group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative "R," "X," "Y," "D," "L," and "Z" groups as set forth above are defined below. These definitions are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure. The term "treatment" as used herein covers any treatment of a disease, disorder, and/or condition in an animal or mammal, particularly a human, and includes: (i) preventing a disease, disorder and/or condition from occurring in a person which can be predisposed to the disease, disorder and/or condition, or at risk for being exposed to an agent that can cause the disease, disorder, and/or condition; but, has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder and/or condition, i.e., arresting its development; and (iii) relieving the disease, disorder and/or condition, i.e., causing regression of the disease, disorder and/or condition.
The term "mimetic" refers to a compound having similar functional and/or structural properties to another known compound or a particular fragment of that known compound, such as a known compound of biological origin, e.g., a polypeptide or fragment thereof.
"Binding specificity" refers to the ability of a protein or other type of molecule capable of recognizing and interacting with a complementary site on another protein or other type of molecule. As used herein, the term binding specificity can refer to the ability of a molecule to bind preferentially to one type of molecule over another. For example, binding specificity can refer the ability of a BDNF mimetic to preferentially bind to TrkB as opposed to TrkA or TrkC. A molecule having binding specificity for a receptor can be used for one or more of contacting the receptor, activating the receptor, and inhibiting the receptor. The term "modulation specificity" as used herein refers to a molecule that can modulate the activity of one receptor preferentially. The molecule can modulate the activity of one receptor to a greater extent than another receptor or can modulate the activity of one receptor in a group of receptors exclusively. For example, a BDNF mimetic can specifically modulate the activity of TrkB and not TrkA or TrkC. The modulation of activity can include, but is not limited to, upregulation, downregulation, activation, partial activation, agonism, partial agonism, antagonism, partial antagonism, inhibition, partial inhibition, or a combination thereof. A molecule having modulation specificity for a receptor can be used, for example, to contact and activate a receptor or to contact and inhibit a receptor. The term "binding and/or modulation specificity" refers to a molecule that can bind a designated receptor, modulate the activity of a designated receptor, or both bind and modulate the activity of a designated receptor.
The term "pharmacophore", as used herein, refers to a molecular moiety capable of exerting a selected biochemical effect, e.g., inhibition of an enzyme, binding to a receptor, chelation of an ion, and the like. A selected pharmacophore can have more than one biochemical effect, e.g., can be an inhibitor of one enzyme and an agonist of a second enzyme. A therapeutic agent can include one or more pharmacophores, which can have the same or different biochemical activities.
The term "derivative" as used herein refers to a compound chemically modified so as to differentiate it from a parent compound. Such chemical modifications can include, for example, replacement of hydrogen by an alkyl, acyl, or amino group. A derivative compound can be modified by, for example, glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the compound from which it was derived.
The terms "small molecule" and "small peptide" refer to compounds having molecular weights below 1000. In some embodiments, the small molecule or small peptide is a compound having a molecular weight below 750. In some embodiments, the small molecule or small peptide has a molecular weight below 500.
The term "peptide" refers to any polymer comprising amino acids linked by amide bonds between the amino group of each amino acid and the carboxyl group of the neighboring amino acid. Each amino acid unit making up the peptide is referred to as a "residue." Thus the term "amino acid residue" refers to the radical or diradical of one of the 20 standard amino acids or of a nonstandard amino acid that results from the loss of a proton from the amine group, the loss of the hydroxyl from the carboxylic acid group, or the loss of both a proton from the amine group and the hydroxyl from the carboxylic acid group. The term "peptide" also refers to derivatives of peptides wherein the amino terminus, the carboxyl terminus, one or more amino acid side chain, or a combination thereof has been chemically modified or derivatized, for example, through acylation, alkylation, reduction, or amidation, or any other method known in the art of peptide chemistry.
The term "stereoisomer" as it relates to a given compound is well understood in the art, and refers to another compound having the same molecular formula, wherein the atoms making up the other compound differ in the way they are oriented in space, but wherein the atoms in the other compound are like the atoms in the given compound with respect to which atoms are joined to which other atoms (e.g., an enantiomer, a diastereomer, or a geometric isomer).
The term "hydrophilicity" is used in the common manner of the field as having an affinity for water; readily absorbing and/or dissolving in water.
The term "lipophilicity" is used in the common manner of the field as having an affinity for, tending to combine with, or capable of dissolving in lipids.
The term "amphipathicity", as used herein, describes a structure having discrete hydrophobic and hydrophilic regions. Thus, one portion of the structure interacts favorably with aqueous and other polar media, while another portion of the structure interacts favorably with non-polar media. The term "solubility" as used herein, describes the maximum amount of solute that will dissolve in a given amount of solvent at a specified temperature.
The term "bioavailability" as used herein refers to the systemic availability (i.e., blood/plasma levels) of a given amount of compound administered to a subject. The term further encompasses the rate and extent of absorption of compound that reaches the site of action.
\l Compounds
The presently disclosed subject matter provides compounds having binding and/or modulation specificity for the TrkB receptor molecule. In some embodiments, the compounds are mimetics of a neurotrophin /Mum loop. In some embodiments, the neurotrophin is BDNF. In some embodiments, the /Murn loop is loop 2 of BDNF. These compounds can be used in accordance with the presently disclosed pharmaceutical compounds and methods in the treatment and prevention of disorders, including but not limited to neurological disorders (e.g., neurodegenerative disorders). Some TrkB binding and/or modulation compounds demonstrate agonist function and thus promote TrkB activation. Some TrkB binding and/or modulation compounds demonstrate partial agonist function. These compounds can be used to promote TrkB function or in some cases to partially block the function of endogenous BDNF. Inhibition of BDNF function can prove useful for prevention or treatment of epilepsy or other disorders in which excessive BDNF function contributes to underlying disease mechanisms. Some TrkB binding and/or modulation compounds demonstrate no agonist activity and thus might prove useful as TrkB antagonists. The TrkB binding and/or modulation compounds of the presently disclosed subject matter can be isolated from natural sources, purchased from commercial sources, or synthesized or partially synthesized by methodology known in the art of synthetic organic chemistry, including parallel and combinatorial synthetic techniques. NA, Structure
In accordance with the presently disclosed subject matter, a representative compound or mimetic of BDNF y?-tum loop 2 having binding and/or modulation specificity for a TrkB receptor molecule can comprise a compound having a structure of one of Formulas (I-XI). In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (I):
Figure imgf000038_0001
wherein:
R1, R2, and R3 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
Xi and X2 are independently selected from CH2 and NR4, wherein R4 is selected from H, alkyl, aralkyl, and aryl; and
Di is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
M
IN
\R 6 , wherein R5 and Re are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt.
In some embodiments, R-i, R2, and R3 are H, Xi and X2 are NH, and Di is alkoxy. In some embodiments, the compound of Formula (I) is
Figure imgf000039_0001
or a stereoisomer thereof.
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (II):
D2 L1 X3 Y1 L2 Y2 X4 L3 D3 (H)
I I
Z1 Z2 wherein: L1 and L3 are independently selected from the group consisting of C1-C5 alkylene, arylene, aralkylene, and substituted arylene;
L2 is selected from the group consisting of C1-C5 alkylene, arylene, aralkylene, substituted arylene,
Figure imgf000040_0001
L4 is C1-C5 alkylene;
Zi, Z2, and Z3 are independently selected from the group consisting of H, alkyl, aryl, and aralkyl;
X3, X4, X5, and X6 are independently N or CH;
Y1, Y2, and Y3 are independently carbonyl, sulfonyi, or methylene; and
D2, D3, D4, and D5 are independently selected from H, alkyl, halo, hydroxyl, mercapto, mercaptoalkyl, alkoxyl, aryloxyl, aralkoxyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dtalkylcarbamoyl,
Figure imgf000040_0002
wherein R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, Li and L3 are C1-C5 alkylene or phenylene. In some embodiments, D2 and D3 are hydroxyl or carbamoyl. In some embodiments, X3 and X4 are N. In some embodiments, the compound of Formula (II) is selected from the group consisting of:
Figure imgf000040_0003
Figure imgf000041_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (III):
Figure imgf000041_0002
wherein:
L5 is present of absent, and when presne is d-Cs alkylene;
X7 and Xs are independently N or CH;
R-io and Rn are independently selected from the group consisting of H, halo, alkyl, and cyano;
D6, D7, and D8 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000041_0003
wherein Rs, R6, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, R-io and Rn are cyano. In some embodiments, D6 is hydroxyl. In some embodiments, D7 is NR5R6. In some embodiments, D8 is acylamino. In some embodiments, the compound of Formula (III) is
Figure imgf000042_0001
In some embodiments, the loop 2 BDNF mimetic has a structure of Formula (IV):
Figure imgf000042_0002
wherein:
X9 and X10 are independently CH2 or NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
R12 is selected from the group consisting of H, alkyl, aralkyl, aryl, acyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
R13 is selected from H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkycarbamoyl, and dialkylcarbamoyl;
R14 and R1S are independently selected from H alkyl, substituted alkyl, and aralkyl; and
R16 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000043_0001
wherein R5 and R6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, Ri2, R13, Ru, and R15 are H or alkyl. In some embodiments, X9 and X10 are NR4. In some embodiments, Ri6 is NR5R6, wherein R5 and R6 are H or alkyl. In some embodiments, the compound of Formula (IV) is
Figure imgf000043_0002
stereoisomer thereof. In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (V):
Figure imgf000043_0003
wherein:
L6 and L7 are independently present or absent, and when present are CrC5 alkylene;
X11 is O, S, CH2 or NR17, wherein R17 is selected from H, alkyl, aralkyl and aryl;
X12, X-I3, and Xi4 are independently CH or N;
Xi5 is selected, from the group consisting of O, S, and NRi8, wherein R18 is selected from H, alkyl, aralkyl, and aryl; and
D9, D10, D11, and D12 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000044_0001
Rs, RQ, Rγ, Re, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, D9, Di0, Dn, and D12 are hydroxyl, alkoxyl or carbamoyl. In some embodiments, the compound of Formula (V) is
Figure imgf000044_0002
or a stereoisomer thereof.
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (Vl):
Figure imgf000044_0003
wherein:
Le is present or absent, and when present is C1-C5 alkylene; X16 is selected from the group consisting of O, S, and NR19, wherein R-ig is selected from H, alkyl, aralkyl and aryl; X17 is selected from the group consisting of O, S, CH2, and NR2O, wherein R2o is selected from H, alkyl, aralkyl, and aryl;
Xi8 and Xi9 are independently selected from N and CH; and
D-13 and Du are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000045_0001
wherein R5, R6, R7, Re, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, D13 and D14 are hydroxyl, alkoxyl, or NR5R6, wherein R5 and R6 are H or alkyl. In some embodiments, the compound of Formula (Vl) is
Figure imgf000045_0002
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (VII):
Figure imgf000046_0001
wherein: m and n are independently 1 or 2; each Lg and l_io can be present or absent, and when present is Ci-C5 alkylene;
X20 and X21 are independently selected from CH, CH2, N, and NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
X22 is selected from H and halo; and each D15 and each D-iβ are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000046_0002
wherein R5, Re, Rz, Re, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, X22 is halo. In some embodiments, each Di5 and each Di6 are hydroxyl. In some embodiments, the compound of Formula (VII) is
Figure imgf000047_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (VIII):
Figure imgf000047_0002
wherein: l_ii is present or absent, and when present is C-1-C5 alkylene;
X23 is N or CH;
R21 and R22 are independently selected from the group consisting of H, alky], aralkyl, aryl and halo; and
Di7, Die, and D19 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000048_0001
wherein Rs, Re, R7, Rs, and Rg are independently selected from H, alky], aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, R2i and R22 are alkyl. In some embodiments, Di7, Die, and Di9 are selected from hydroxyl, alkoxyl, and carbamoyl. In some embodiments, the compound of Formula (VIII) is selected from the group consisting of:
Figure imgf000048_0002
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (IX):
Figure imgf000049_0001
wherein:
L12 is present or absent, and when present is Ci-C5 alkylene;
X24 is N or CH;
R23 is selected from the group consisting of H, alkyl, aralkyl, aryl, and halo; and
D2O, D2i, D22, D23, and D23 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000049_0002
wherein R5, R6, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, D20, D2i, D22, D23, and D24 are selected from hydroxyl, alkoxyl, halo, and carbamoyl. In some embodiments, R23 is alkyl. In some embodiments, the compound of Formula (IX) is
Figure imgf000049_0003
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (X):
Figure imgf000050_0001
wherein: t is 1 or 2; each L-I3 is present or absent, and when present is C1-C5 alkylene;
X25 and X26 are selected from N and CH;
X27 is selected from N, CH, CH2, and NR25, wherein R25 is H or alkyl;
R24 is selected from H, alkyl, aralkyl, aryl, and halo; and
D25 and each D26 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000050_0002
wherein R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, D25 and each D2β are selected from hydroxyl and alkoxyl. In some embodiments, R24 is alkyl. In some embodiments, the compound of Formula (X) is
Figure imgf000051_0001
In some embodiments, the loop 2 BDNF mimetic compound has a structure of Formula (Xl):
Figure imgf000051_0002
wherein:
X28 is selected from CH2, O, S, and NR26, wherein R26 is selected from H, alkyl, aralkyl, and aryl;
X29 is N or CH;
X30 is CH2 or NR27; wherein R27 is selected from H, alkyl, aralkyl, and aryl;
X31 is N or CH; and
D27, D28, and D2g are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000051_0003
wherein R5, Re, R7, Rs, and Rg are independently selected from H1 alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
In some embodiments, D27, D28, and D29 are independently hydroxy! or alkoxyl. In some embodiments, the compound of Formula (Xl) is
Figure imgf000052_0001
The compounds disclosed herein can also encompass derivatives of a parent compound, which has binding and/or modulation specificity for a TrkB receptor molecule, wherein the derivative also has binding and/or modulation specificity for the TrkB receptor. The derivative can exhibit enhancement in at least one of the characteristics selected from the group consisting of hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound. In some embodiments, the compound is a derivative of a parent compound having binding and/or modulation specificity for a TrkB receptor molecule, wherein the derivative is transformed in vivo to the parent compound or to another derivative of the parent compound that also has binding and/or modulation specificity for the TrkB receptor. Such derivatives can be referred to in some embodiments as prodrugs. Prodrugs can contain bonds that hydrolyze in vivo chemically (i.e., hydrolysis catalyzed by changes in pH) or enzymatically. Such bonds include, but are not limited to, esters, amides, and carbonates. Hydrolysis of such a bond in vivo can reveal, for example, a hydrogen donor moeity, such as an alcohol or an amine.
It is to be understood that in some embodiments the compounds disclosed herein can encompass a pharmacophore substantially identical to the pharmacophore illustrated in Figure 1. Representative such compounds include, but are not limited to, compounds encompassed by Formulae (I-XI). II.B. Formulations
The compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.
For example, formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients to control the release of active compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
Further, formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
Formulations of the compounds can contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The formulations comprising the compound can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The compounds can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrollidone, sodium saccharine, cellulose, magnesium carbonate, etc.
The pharmaceutical formulations comprising the compounds of the presently disclosed subject matter can include an agent which controls release of the compound, thereby providing a timed or sustained release compound.
II. C. Carriers
Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
Examples of non-aqueous solvents suitable for use in the presently disclosed subject matter include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
Aqueous carriers suitable for use in the presently disclosed subject matter include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.
Liquid carriers suitable for use in the presently disclosed subject matter can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
Liquid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent. Solid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Parenteral carriers suitable for use in the presently disclosed subject matter include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
Carriers suitable for use in the presently disclosed subject matter can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art. II.D. Salts
It is also to be understood that the disclosed compounds can further comprise pharmaceutically acceptable salts.
Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates and the like. Base addition salts include but are not limited to, ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N, N1- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl)- aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g. , lysine and arginine dicyclohexylamine and the like.
Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.
Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. 11.E. Tracers
In some embodiments of the presently disclosed subject matter, the BDNF mimetic comprises a tracer or label that can be detected in vivo (i.e., in a living subject) or in vitro (i.e., outside a living subject). In some embodiments, the tracer is detectable in vivo by a non-invasive method, including, but not limited to, scintigraphic methods, magnetic resonance imaging, ultrasound, or fluorescence. The tracer can be conjugated or otherwise associated with a BDNF mimetic, a drug carrier, or combinations thereof. Following administration of the labeled composition to a subject, and after a time sufficient for localization in vivo, the biodistribution of the composition can be visualized. For example, a BDNF mimetic labeled with a radioactive tracer can be used to detect tumors or other pathological states with altered TrkB expression in vivo.
In some embodiments, the label is detectable by a scintigraphic imaging method. Scintigraphic imaging methods include SPECT (Single Photon Emission Computed Tomography), PET (Positron Emission Tomography), gamma camera imaging, and rectilinear scanning. A gamma camera and a rectilinear scanner each represent instruments that detect radioactivity in a single plane. Most SPECT systems are based on the use of one or more gamma cameras that are rotated about the subject of analysis, and thus integrate radioactivity in more than one dimension. PET systems comprise an array of detectors in a ring that also detect radioactivity in multiple dimensions.
When scintigraphic imaging is employed, the detectable tracer or label can comprise a radionuclide label selected from the group consisting of, but not limited to, 18fluorine, 64copper, 65copper, 67gallium, 68gallium, 77bromine, 80mbromine, 95ruthenium, 97ruthenium, 103ruthenium, 105ruthenium, "technetium, 107mercury, 203mercury, 123iodine/ 124iodine, 125iodine, 126iodine, 131iodine, 133iodine, 111indium, 113mindium, 99mrhenium, 105rhenium, 101rhenium, 186rhenium, 188rhenium, 121mtellurium, 122mtellurium, 125mtellurium, 165thulium, 167thulium, 168thulium, and nitride or oxide forms derived there from. Methods for radionuclide-labeling of a molecule so as to be used in accordance with the disclosed methods are known in the art. For example, a BDNF mimetic can be derivatized so that a radionuclide can be bound directly to it. Thus, the radionuclide can take the place of a hydrogen atom of one of the BDNF mimetics described herein in Formulas (I-XI). Alternatively, the radionuclide or radioactive tracer can be bound to a BDNF mimetic of Formulas (I-XI) through a suitable organic tether moiety, such as an alkylene group.
When compositions comprising radionuclides are used, stabilizers to prevent or minimize radiolytic damage, such as ascorbic acid, gentisic acid, or other appropriate antioxidants, can be added to the composition comprising the labeled targeting molecule.
ML Methods of Use
The presently disclosed subject matter provides novel methods of treating disorders, including, but not limited to, neurological disorders (e.g., neurodegenerative disorders) and in a subject. More particularly, the methods of the presently disclosed subject matter involve the administration of a compound having binding and/or modulation specificity for a TrkB receptor molecule in a subject to treat a disorder. The compound can be administered in an amount effective to induce survival signaling and/or to upregulate neural function. The compound can also be used to stimulate desired mechanisms of non-neural cells. The compound can also be used to partially or fully block endogenous BDNF.
The disorder to be treated can be any condition that is mediated, at least in part, by binding of neurotrophins to the TrkB receptor, and conditions wherein the TrkB receptor is present, though not necessarily causally linked to the condition. Neurotrophins can be present or absent in the condition. Such disorders include, but are not limited to, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications, multiple sclerosis, peripheral nerve injury, conditions involving degeneration or dysfunction of cells expressing TYkB. The disorder to be treated further includes depression, obesity, and ischemic conditions of peripheral tissues. Table 1 lists a variety of disorders to which TrkB involvement has been linked.
Figure imgf000060_0001
Figure imgf000061_0001
The presently disclosed subject matter further provides for methods of facilitating cell survival or function, including both neural cells and non-neural cells. Representative neural cells include, but are not limited to, hippocampal pyramidal cells, cortical cells, striatal cells, substantial nigra cells, motor neuron cells, Purkinje cells, dorsal root ganglia cells. Non- neuronal cells include, but are not limited to, vascular endothelial cells. The methods can comprise treating a neural or non-neural cell with a compound having binding or modulation specificity for a TrkB receptor molecule, whereby the compound induces survival signaling and/or upregulation of cell function.
The BDNF mimetics of Formulas (I-XI) can be used in both in vivo and in vitro settings. In some embodiments, the BDNF mimetics can be used as a cost saving alternative to BDNF in in vitro methods. In some embodiments, the BDNF mimetics can be used in methods related to stem cells. Thus, in some embodiments, the BDNF mimetics can be used for maintaining stem cells in an undifferentiated state or to induce stem cell differentiation. By way of example, a BDNF mimetic as disclosed herein can be used in methods currently available in the art that employ BDNF (Huang, E.J., Reichardt LF. (2003) Annu Rev Biochem 72, 609-642; Banker, G., Goslin, K. (Eds.) (1998) Culturing Nerve Cells, Chapters 10 and 14 (Cambridge, Massachusetts: The MIT Press)), except with the substitution of the BDNF mimetic.
IHA Administration
The presently disclosed subject matter provides methods of administering compounds having binding and/or modulation specificity for a TrkB receptor compound in order to ameliorate a disorder mediated by TrkB binding or modulation in a subject. The method can comprise administering to a subject an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor, such as any of the compounds disclosed herein.
As used herein, administering can be effected or performed using any of the various methods known to those skilled in the art. The compound can be administered, for example, subcutaneously, intravenously, parenterally, intraperitoneally, intradermal^, intramuscularly, topically, enteral (e.g., orally), rectally, nasally, buccaily, sublingually, vaginally, by inhalation spray, by drug pump or via an implanted reservoir in dosage formulations containing conventional non-toxic, physiologically acceptable carriers or vehicles.
Further, the presently disclosed compounds can be administered to a localized area in need of treatment. This can be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, transdermal patches, by injection, by catheter, by suppository, or by implant (the implant can optionally be of a porous, non-porous, or gelatinous material), including membranes, such as sialastic membranes or fibers.
The form in which the compound is administered (e.g., syrup, elixir, capsule, tablet, solution, foams, emulsion, gel, sol) will depend in part on the route by which it is administered. For example, for mucosal (e.g., oral mucosa, rectal, intestinal mucosa, bronchial mucosa) administration, nose drops, aerosols, inhalants, nebulizers, eye drops or suppositories can be used. The compounds and agents disclosed herein can be administered together with other biologically active agents, such as analgesics, anti- inflammatory agents, anesthetics and other agents which can control one or more symptoms or causes of a TrkB mediated disorder.
Additionally, administration can comprise administering to the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods, upon a review of the instant disclosure.
In some embodiments, administration comprises administering to the subject a dose or plurality of dosages to achieve a compound concentration in a cell or in a cell microenvironment of between about 0.10 μM and about 50 μM.
The compounds of the presently disclosed subject matter can be employed as the sole active agent in a pharmaceutical or can be used in combination (e.g., administered proximate in time to each other or even in the same formulation) with other active ingredients, e.g., neurotrophins, or other factors or drugs which can facilitate neural survival or axonal growth in neurodegenerative diseases. For example, synergistic effects can be provided by administering a compound having binding and/or modulation specificity for a TrkB receptor molecule to a subject with a second compound having binding and/or modulation specificity for a p75NTR receptor molecule. Representative compounds having binding specificity for p75NTR receptor molecules are disclosed in U.S. Patent Application Serial No. 11/396,936, filed April 3, 2006, herein incorporated by reference in its entirety. 111. B. Dosage For administration of a compound as disclosed herein, conventional methods of extrapolating human dosage based on doses administered to a murine animal models can be carried out using the conversion factor for converting the mouse dosage to human dosage: Dose Human per kg=Dose Mouse per kg*12 (Freireich et al., (1966) Cancer Chemother Rep. 50, 219- 244). Drug doses can also be given in milligrams per square meter of body surface area rather than body weight, as this method achieves a good correlation to certain metabolic and excretionary functions. Moreover, body surface area can be used as a common denominator for drug dosage in adults and children as well as in different animal species (Freireich et a/., (1966) Cancer Chemother Rep. 50, 219-244). Briefly, to express a mg/kg dose in any given species as the equivalent mg/sq m dose, the dosage is multiplied by the appropriate km factor. In an adult human, 100 mg/kg is equivalent to 100 mg/kg *37 kg/sq m=3700 mg/m2.
Insofar as the compounds disclosed herein can take the form of a mimetic or fragment thereof, it is to be appreciated that the potency, and therefore dosage of an effective amount can vary. However, one skilled in the art can readily assess the potency of a compound of the type presently envisioned by the presently disclosed subject matter.
The compounds disclosed herein can be used in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art, or example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980). It will be appreciated by one of skill in the art that dosage range will
• depend on the particular compound, and its potency. The dosage range is understood to be large enough to produce the desired effect in which the neurological disorder and the symptoms associated therewith are ameliorated and/or survival of the neural cells is achieved, but not be so large as to cause unmanageable adverse side effects. The appropriate range for therapeutic effectiveness will be readily determined by one skilled in the art depending on the route of administration, age, and condition of the subject being treated. The dosage can also be adjusted by the individual physician in the event of any complication. No unacceptable toxicological effects are expected when compounds disclosed herein are used in accordance with the presently disclosed subject matter.
An effective amount of the compounds disclosed herein comprise amounts sufficient to produce a measurable biological response. Actual dosage levels of active ingredients in a therapeutic compound of the presently disclosed subject matter can be varied so as to administer an amount of the active compound that is effective to achieve the desired therapeutic response for a particular subject and/or application. Preferably, a minimal dose is administered, and the dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of a therapeutically effective dose, as well as evaluation of when and how to make such adjustments, are known to those of ordinary skill in the art.
Further with respect to the methods of the presently disclosed subject matter, a preferred subject is a vertebrate subject. A preferred vertebrate is warm-blooded; a preferred warm-blooded vertebrate is a mammal. The subject treated by the presently disclosed methods is desirably a human, although it is to be understood that the principles of the presently disclosed subject matter indicate effectiveness with respect to all vertebrate species which are to included in the term "subject." In this context, a vertebrate is understood to be any vertebrate species in which treatment of a neurodegenerative disorder is desirable. As used herein, the term "subject" includes both human and animal subjects. Thus, veterinary therapeutic uses are provided in accordance with the presently disclosed subject matter.
As such, the presently disclosed subject matter provides for the treatment of mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and/or animals of social importance to humans, such as animals kept as pets or in zoos. Examples of such animals include but are not limited to: carnivores such as cats and dogs; swine, including pigs, hogs, and wild boars; ruminants and/or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; and horses. Also provided is the treatment of birds, including the treatment of those kinds of birds that are endangered and/or kept in zoos or as pets (including parrots), as well as fowl, and more particularly domesticated fowl, i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economical importance to humans. Thus, also provided is the treatment of livestock, including, but not limited to, domesticated swine, ruminants, ungulates, horses (including race horses), poultry, and the like. III.C. Coatings
In some embodiments, the compounds of the presently disclosed subject matter can be used in coatings. For example, the BDNF mimetics of Formulas (I-XI) can be used to coat medical devices, such as surgical tools, biosensors, and implants, to promote neural and/or non-neural cell survival in tissues or fluids coming into contact with the medical device or to treat a pathological state with altered TrkB expression in an area in contact with the medical device. In some embodiments, the medical device is a cochlear implant, an electronic device interfacing with the nervous system, or a synthetic matrix designed to support neural regeneration.
The mimetics can be coated onto the medical devices by a variety of methods. For example, the mimetics can be suspended or dissolved in a liquid carrier, coated and dried onto the medical device. Alternatively, the mimetics can be conjugated to a chemically funtionalized surface of a device or imbedded in or conjugated to a polymeric coating of a medical device. In some embodiments, the device being coated can have a metallic surface, such as, for example, stainless steel, nickel, titanium, aluminum, copper, gold, silver, platium, and combinations thereof. In some embodiments, the device can have a glass or polymeric surface.
EXAMPLES
The following Examples have been included to provide illustrations of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications and alterations can be employed without departing from the spirit and scope of the presently disclosed subject matter. MATERIALS AND METHODS FOR EXAMPLES Computational studies
Computational studies were performed using the Accelrys Catalyst® and INSIGHT II™ systems obtained from Accelerys (San Diego, California, United States of America). Antibodies and Proteins
Monoclonal anti-phospho-ERKT202/Y204, polyclonal anti-ERK42/44, monoclonal anti-phospho-AKTs473, polyclonal anti-AKT, polyclonal anti- phospho-NF/cB-p65(Ser563), and site-specific polyclonal anti-TrkY490 were obtained from Cell Signaling Technology, Inc. (Beverly, Massachusetts, United States of America). Monoclonal anti-actin was obtained from Sigma- Aldrich Corp. (St. Louis, Missouri, United States of America). Polyclonal TrkA and TrkB antibodies were obtained from Upstate USA, Inc. (Charlottesville, Virginia, United States of America). Recombinant human NGF was obtained from Invitrogen (Carlsbad, California, United States of America) and BDNF from Sigma-Aldrich (St. Louis, Missouri, United States of America).
Hippocampal neurons were prepared from E16-17 mouse embryos as previously described (Yang, T. et a/. (2003) J Neurosci 23, 3353-3363). Low density cultures were initiated in poly-L-lysine coated A/2 plates by adding 25 μ\ of cell suspension (2000 neurons/well; 12,500 cells/cm2), 25 μ\ of DMEM containing 10% FBS, and different concentrations of recombinant BDNF, NGF, or TrkB-binding compounds to each well.
After 48 hours in culture, cell survival was assessed as previously described (Longo, F.M., Manthorpe, M., Xie, Y.M., Varon, S. (1997) J Neurosci Res 48, 1-17) using a combination of standard morphological criteria along with visual determination of whether a given cell converted MTT to its blue formazan product. Briefly, the number of surviving neurons was determined by counting the total number of cells in each well that were both morphologically intact and filed with blue product (Lonqo F.M.. Manthorpe, M., Xie, Y.M., Varon, S. (1997) J Neurosci Res 48, 1-17). For each neurotrophin or compound concentration, duplicate wells were counted and the resulting values averaged. Activity of each compound was confirmed by blinded counts. Counts were normalized to survival achieved with 25 ng/ml BDNF or to baseline survival. Fitting of dose-responsive curves was performed with SIGMAPLOT™ obtained from SYSTAT Software Inc. (Richmond, California, United States of America).
For signaling pathway inhibitor studies, LY294002, PD98059 (obtained from EMD Biosciences/Calbiochem, San Diego, California, United States of America), were added to cultures at final concentrations of 25 μM, 50 μM, and 2.5 μg/ml respectively, concomitantly with BDNF or TrkB-binding compounds. For all studies applying signaling inhibitors, survival was assessed at 48 hours. Protein Extraction and Western Blot Analysis
For assays of Trk, AKT, and ERK activation, hippocampal neurons derived from E16-17 mice were cultured in poly-L-lysine coated six-well plates (Corning, Inc., Corning, New York, United States of America) in DMEM containing 10% FBS, followed by incubation in serum-free DMEM for 2 hours before addition of neurotrophins or compounds. At the indicated time points, neurons were harvested in lysis buffer consisting of: 20 mM Tris, pH 8.0, 137 mM NaCI, 1 % lgepal CA-630, 10% glycerol, 1 mM PMSF, 10 μg/ml aprotinin, 1 μg/ml leupeptin, 500 μM orthovanadate (Zhou, J., Valletta, J.S., Grimes, M. L., Mobley, W.C. (1995) J Neurochem 65, 1146-1156). Lysates were centrifuged, the supernatant collected, and protein concentrations determined using the BCA Protein Assay Reagent obtained from Pierce (Rockford, Illinois, United States of America). Western blots were performed as described previously (Yang, T. et al.
(2003) J Neurosci 23, 3353-3363). Western blot signals were detected using the ECL Chemiluminescence System obtained by Amersham (Piscataway, New Jersey, United States of America) (Yang, T. et al. (2003) J Neurosci 23, 3353-3363). To detect the presence of anti-Trk antibodies, blots were probed with horseradish peroxidase-linked goat anti-rabbit IgG obtained from Amersham/Pharmacia Biotech (Piscataway, New Jersey, United States of America). Signals were detected by the ECL chemiluminescence system obtained from Amersham Biosciences (Piscataway, New Jersey, United States of America). To control for variation in protein loading, the blot was stripped and reprobed with /?-actin monoclonal antibody obtained from Sigma (St. Louis, Missouri, United States of America).
Example 1
Computational Modeling, Pharmacophore Generation, Virtual and Functional Screening In order to generate a productive pharmacophore emulating a loop structure known to interact with a receptor, it was hypothesized that (1) the degrees of freedom of the ligand peptide structure are restricted by its residence in the protein, and (2) there is little "induced fit" involving changes in loop structure at the targeted receptor subsite, or it is accommodated by flexibility of the small molecule ligand. When both of these conditions apply, they allow an interacting/activating small molecule conformation that interacts with the receptor in a manner similar to that of the native ligand.
Efforts were focused on locating compounds emulating a single loop BDNF loop 2 structure. Computational studies suggested that in situ, the tethered loop 2 backbone and proximal portions of the side chain structure had restricted degrees of freedom, and an intermediate structure chosen from an ensemble of samples from loop molecular dynamics simulations was extracted and used to build a pharmocophoric model. The residues involved with the pharmacophore were Ser45, Lys46 and Gln48 of BDNF (Figure 1 ). Guidance for the placement of pharmacophore features was obtained from consideration of loop phylogeny and side chain chemistry.
An average of 35 conformers of each of over 5.5 million compounds compounds were screened against the pharmacophore, yielding approximately 3000 that fit with a calculated internal energy of less than 10 kcal/mol. This number was reduced to approximately 50 by visual inspection, calculated blood brain barrier penetration and other predicted medicinal properties on the basis of likely steric compatibility with a hypothetical shallow receptor binding pocket, and maximal flexibility of the functional groups.
Example 2 Compounds Promote Hippocampal Neuron Survival
High-throughput virtual screening based on BDNF loop 2 models (Figure 1 ) and small-scale in vitro bioassays were used to identify chemically diverse compounds with potent neurotrophic activity. Approximately 5.5 million compounds were screened in silico to produce a high yield of 15 positives out of 32 compounds submitted to in vitro screening (47%).
In order to understand the mechanisms of action of the BDNF loop 2 mimetics and to test the conjecture that they work via the targeted receptor, TrkB, the dose-dependent relationships of the survival-promoting activities of the mimetics was compared to BDNF using embryonic hippocampal neurons in culture conditions in which BDNF promotes neural survival. In the cultures, neurotrophic activity was mediated by BDNF principally through TrkB and p75NTR, as they express little TrkA (Brann. A.B., et a/. (1999) J Neurosci 19, 8199-8206; Bui, NT., et al. (2002) J Neurochem 81, 594- 605). Studies indicated that Compound 4 (BD2-4) prevents the death of
E16 hippocampal neurons and that neurite outgrowth length promoted by Compound 4 was similar to that seen with BDNF. See Figure 2. Dose- response profiles of Compounds 1-4 (BD2-1 , BD2-2, BD2-3, and BD2-4, respectively; Figure 3A-E) demonstrated EC5O values in the range of 0.1-1.0 nM and intrinsic activities of 50-200% of the BDNF response. Additionally, as predicted for a partial agonist, Compound 4 in the presence of a maximally effective BDNF concentration (50 ng/mL) causes an inhibition of BDNF activity. See Figure 4. The structures of Compounds 1-4 are illustrated in Table 2 below. Table 2 Structures of Compounds 1-4
Figure imgf000071_0001
Of the four compounds initially identified, one, Compound 4, is predicted to have the most "drug-like" character by the Lipinski criteria (Lipinski, CA. (2000) J Pharm Toxicol Methods 44, 235-249) and blood- brain barrier calculations (Fu, X.C., Chen, CX, Liang, W.Q., Yu, Q. S. (2001 ) Acta Pharmacol Sin 22, 663-668; Clark, D. E. (2002) J Pharm Sci 88, 815- 821 ). As such, Compound 4 was selected for more detailed mechanistic study.
Example 3 Compounds Activate TrkB Receptors,
In order to assess the interactions of the BDNF loop 2 mimetic compounds with TrkB receptors, the ability of Compound 4 to activate TrkA, TrkB, and TrkC was compared in a series of Western blotting experiments. These studies demonstrate that the BDNF mimetics achieve a high level of specificity in that only TrkB is activated.
The top two panels in Figure 5A show that in NIH3T3 cells expressing TrkB, both BDNF and Compound 4 (BD2-4) activate TrkB as evidenced by Trk phosphorylation (indicated by probing with anti-TrkY490 antibodies in the uppermost panel). Culture medium alone (CM) or treatment with NGF does not activate TrkB. The second panel from the top shows the Western blot with anti-TrkB antibodies indicating the total amount of TrkB present. In the bottom two panels of Figure 5A, NIH3T3 cells expressing TrkA were used. NGF promotes activation of TrkA as evidenced by Trk phosphorylation, but BDNF and Compound 4 do not. In Figure 5B, NIH3T3 cells expressing TrkC were used. The bottom panel indicates the total amount of TrkC present by probing with anti-TrkC antibodies. NT-3 promotes the phosphorylation of Trk (upper panel), while culture medium alone (CM), BDNF, and Compound 4 do not.
Example 4
Compound Activity in Huntington's Disease Model Quinolinic acid-induced death of striatal neurons is an established model for Huntington's disease (HD). Previous work has shown that BDNF functions are impaired in HD and that administration of BDNF can prevent quinolinic acid-induced death. See Perez-Navarro, E., et a/, (2000) J. Neurochem 75, 2190-2199; and KeIIs. A. P., et a/. (2004) MoI Ther 9, 682- 688, each of which is herein incorporated by reference in its entirety. As shown in Figure 6A, application of quinolinic acid at 7.5 mM leads to death of approximately 50% of mouse E16 striatal neurons comparing culture medium alone (CM) to quinolinic acid in the absence of BDNF, over a dose range of 0 to 1.5 ng/mL, and BD2-4, over a dose range of 10-1000 nM, demonstrate similar efficacies in decreasing quinolinic acid-induced death. The K252a inhibitor is a well-characterized inhibitor of TrkB receptor activation. As shown in Figure 6B, K252a had no effect on quinolinic acid- induced death but did block the ability of BDNF and BD2-4 to prevent death. These findings confirm that the BD2-4 effect is mediated through its ability to activate the TrkB receptor. A study similar to the one shown in Figure 6B was conducted in which only DARP32-positive neurons were assessed. DARP32-positive neurons represent the population within the striatum that are particularly vulnerable in HD. As shown in Figure 6C, BD2-4 protects DARP32 — positive neurons with an efficacy similar to that of BDNF. Figure 6C further demonstrates that this protection is mediated through TrkB and that the efficacy of BD2-4 is similar to that of BDNF. As in Figure 6B, the addition of the inhibitor K252a decreased the ability of BDNF and BD2-4 to prevent cell death (Figure 6C).
Example 5 Compound Activity in Parkinson's Disease Model
Exposure of SH-SY5Y cells to 1-methyl-4-phenylpyridinium (MPP+) with resulting cell death is a well-characterized model of Parkinson's disease (PD). See Presqraves, S.P., et a/. (2004) Exp Neurol 190, 157-170, and Dluzen, D.E., et al. (2004) Neuroscience 128, 201-208, each of which is herein incorporated by reference in its entirety. BDNF has also been previously shown to protect dopaminergic neurons. Further, MPP+ causes a PD-like condition in primates. For the Parkinson's disease model assays, human SH-SY5Y cells were used after terminal differentiation into a dopaminergic phenotype (Presqraves, S. P., et a/. (2004) Exp Neruol 190, 157-170). Human SH- SY5Y neuroblastoma cells were propagated to confluence in Dulbecco's Modified Eagle's media (DMEM) supplemented with 10% fetal calf serum, 100μg/mL penicillin, 100μg/ml_ streptomycin, 0.25μg/ml_ amphotericin B, and 0.01 μM non-essential amino acids and then sub-cultured for differentiation. For differentiation, the cells were incubated in same media containing 10 μM retinoic acid for 3 days; then the media was removed and replaced with media containing 160 nM of the phorbol ester 12-0- tetradecanoyl-phorbol-13-acetate (TPA) for 3 days of differentiation. The cells were then administered a range dose of BD2-4 or BDNF (1 x10'12 M to 1 mM) in DMEM for 30 mins for three days prior to addition of 100 μM MPP+. Following transfer of MPP+ to the media, sister cultures were tested at 6, 12, 24, and 48 hrs for the cytotoxicity of MPP+ as measured by the MTT and lactate dehydrogenase method (LDH) assays which accurately measure different aspects of cell death. In addition, the neuroprotective effects of a fixed dose of BD2-4 and BDNF on MPP+ induced cell death were tested for in the presence and absence of TrkB inhibitor K252a (200 nM). As shown in Figure 7, the TrkB inhibitor K252a has a small effect on lowering cell survival of dopaminergic neurons. MPP+ promotes death of essentially all cells. The death-inducing activity of MPP+ is significantly blocked to a similar extent by both BDNF and BD2-4. K252a blocks a significant amount of the protection afforded by BDNF and BD2-4, indicating that this protective effect is mediated through the activation of TrkB. Mean + SE are shown.
Example 6
Compound Activity in Alzheimer's Disease Model The ability of the BDNF mimetics to prevent A/?-induced neuronal degeneration was tested as a model of the compounds' ability to treat Alzheimer's disease. E16-17 hippocampal neurons were matured for 6 days and then incubated for 3 days with the indicated combinations of Aβ oligomer preparations (Dahlαren. K.N., et a/. (2002) J Biol Chem 277, 32046-32053), neurotrophins and neurotrophin mimetics. Following the three day incubation, neuronal survival was assessed using standard morphological criteria (Massa, S.M., et a/. (2006) J Neurosci 26, 5288- 5300.).
As shown in Figure 8, addition of A/?i-42 oligomer (10 μM) but not control A/?Scrambied oligomer (10 μM) resulted in an approximate 40% reduction in neuronal survival. NGF failed to prevent A/?-induced degeneration. NGF mimetic LM11A-31 , known to act as a ligand at the NGF p75NTR receptor (described in U. S. Patent Application Serial No. 11/396,936, filed April 3, 2006), blocked A/?-induced degeneration. This blocking activity was itself blocked by NGF, consistent with NGF competing with LM11A-31 at the p75NTR receptor and thereby inhibiting its protective effect. BDNF mimetics BD2-4 (Compound 4) and BD2-24 (Compound 24) were as effective as BDNF in blocking A/?-induced degeneration. These studies demonstrate for the first time that BDNF can block Aβ oligomer- induced degeneration and that BDNF mimetics are equally as effective in blocking the A/? oligomer-induced degeneration as BDNF protein.
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It will be understood that various details of the presently claimed subject matter can be changed without departing from the scope of the presently claimed subject matter. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.

Claims

CLAIMS What is claimed is:
1. A method of treating a disorder that can be treated by contacting, activating or inhibiting a TrkB receptor in a subject in need of treatment thereof, comprising administering to the subject an effective amount of a compound having binding and/or modulation specificity for a TrkB receptor molecule, thereby treating the disorder.
2. The method of claim 1 , wherein the disorder is selected from, but not limited to, the group consisting of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Rett syndrome, epilepsy, Parkinson's disease, spinal cord injury, stroke, hypoxia, ischemia, brain injury, diabetic neuropathy, peripheral neuropathy, nerve transplantation complications, motor neuron disease, multiple sclerosis, HIV dementia, peripheral nerve injury, hearing loss, depression, obesity, metabolic syndrome, pain, cancer, and other conditions involving degeneration or dysfunction of cells expressing TrkB.
3. The method of claim 1 , wherein the subject is a human subject.
4. The method of claim 1 , wherein the compound is a mimetic of a brain- derived neurotrophic factor (BDNF) /Murn loop.
5. The method of claim 4, wherein the compound comprises a pharmacophore substantially identical to the pharmacophore illustrated in
Figure 1.
6. The method of claim 4, wherein the compound is a small molecule.
7. The method of claim 4, wherein the BDNF /?-tum loop is loop 2.
8. The method of claim 7, wherein the compound has a structure of Formula (I):
Figure imgf000080_0001
wherein:
R-i, R2, and R3 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
Xi and X2 are independently selected from CH2 and NR4, wherein R4 is selected from H, alkyl, aralkyl, and aryl; and
D1 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000080_0002
, wherein R5 and R6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt thereof.
9. The method of claim 8, wherein the compound has the structure:
Figure imgf000080_0003
or a stereoisomer thereof.
10. The method of claim 7, wherein the compound has a structure of Formula (II):
D2-L1- -X 3-Yr "U-Y0-X4-L, -D,
(II)
wherein:
Li and L3 are independently selected from the group consisting of C1-Ce alkylene, arylene, aralkylene, and substituted arylene;
L2 is selected from the group consisting of C1-C5 alkylene, arylene, aralkylene, substituted arylene,
Figure imgf000081_0001
L4 is CrC5 alkylene;
Z-I, Z2, and Z3 are independently selected from the group consisting of H, alkyl, aryl, and aralkyl;
X3, X4, X5, and Xε are independently N or CH;
Yi, Y2, and Y3 are independently carbonyl, sulfonyl, or methylene; and
D2, D3, D4, and D5 are independently selected from H, alkyl, halo, hydroxyl, mercapto, mercaptoalkyl, alkoxyl, aryloxyl, aralkoxyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000081_0002
wherein R5, RQ, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
11. The method of claim 10, wherein the compound is selected from the group consisting of:
Figure imgf000082_0001
Figure imgf000082_0002
12. The method of claim 7, wherein the compound has a structure of Formula (III):
Figure imgf000082_0003
wherein:
L5 is present or absent, and when present is Ci-C5 alkylene; X7 and Xs are independently N or CH; Rio and Rn are independently selected from the group consisting of H, halo, alkyl, and cyano;
DQ, D7, and D8 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000083_0001
wherein R5, Re, R7, Re, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
13. The method of claim 12, wherein the compound is
Figure imgf000083_0002
14. The method of claim 7, wherein the compound has a structure of Formula (IV):
Figure imgf000083_0003
wherein: Xg and Xio are independently CH2 or NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
Ri2 is selected from the group consisting of H, alkyl, aralkyl, aryl, acyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl; R-I3 is selected from H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkycarbamoyl, and dialkylcarbamoyl;
Ri4 and Ri5 are independently selected from H alkyl, substituted alkyl, and aralkyl; and Ri6 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000084_0001
wherein R5 and Re are H, alkyl, aralkyl, or aryl. or a pharmaceutically acceptable salt thereof.
15. The method of claim 14, wherein the compound is
Figure imgf000084_0002
or a stereoisomer thereof.
16. The method of claim 7, wherein the compound has a structure of Formula (V):
(V)
Figure imgf000084_0003
wherein: L6 and L7 are independently present or absent, and when present are C1-Cs alkylene;
Xii is O, S, CH2 or NRi7, wherein R-17 is selected from H, alkyl, aralkyl and aryl; X12, X13, and X14 are independently CH or N;
X15 is selected from the group consisting of O, S, and NR1S, wherein R1S is selected from H, alkyl, aralkyl, and aryl; and
D9, D10, D11, and Di2 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000085_0001
R5, RΘ, R7> Re, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein the compound is
Figure imgf000085_0002
or a stereoisomer thereof.
18. The method of claim 7, wherein the compound has a structure of Formula (Vl):
Figure imgf000086_0001
wherein:
Le is present or absent, and when present is C1-C5 alkylene;
X16 is selected from the group consisting of O, S, and NR19, wherein R-19 is selected from H, alkyl, aralkyl and aryl;
X17 is selected from the group consisting of O, S, CH2, and NR20, wherein R2o is selected from H, alkyl, aralkyl, and aryl;
Xi8 and X19 are independently selected from N and CH; and
D13 and D14 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000086_0002
wherein R5, Re, R7, R8 , and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
19. The method of claim 18, wherein the compound is
Figure imgf000087_0001
20. The method of claim 7, wherein the compound has a structure of Formula (VII):
Figure imgf000087_0002
wherein: m and n are independently 1 or 2; each L9 and Li o can be present or absent, and when present is C1-C5 alkylene;
X20 and X21 are independently selected from CH, CH2, N, and NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
X22 is selected from H and halo; and each D15 and each Di6 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000088_0001
wherein R5, R6, R7, Re, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
21. The method of claim 20, wherein the compound is
Figure imgf000088_0002
22. The method of claim 7, wherein the compound has a structure of Formula (VIII):
Figure imgf000088_0003
wherein:
Li 1 is present or absent, and when present is C1-Cs alkylene; X23 is N or CH; R21 and R22 are independently selected from the group consisting of H, alkyl, aralkyl, aryl and halo; and
Di7, Die, and D19 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000089_0001
wherein R5, Re, R7, Rs, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
23. The method of claim 22, wherein the compound is selected from the group consisting of:
Figure imgf000089_0002
Figure imgf000090_0001
24. The method of claim 7, wherein the compound has a structure of Formula (IX):
Figure imgf000090_0002
wherein:
[_12 is present or absent, and when present is C1-C5 alkylene;
X24 is N or CH;
R23 is selected from the group consisting of H, alkyl, aralkyl, aryl, and halo; and
D20, D21, D22, D23, and D23 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000090_0003
wherein R5, Re, R7, R8, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
25. The method of claim 24, wherein the compound is
Figure imgf000091_0001
26. The method of claim 7, wherein the compound has a structure of Formula (X):
Figure imgf000091_0002
wherein: t is 1 or 2; each Lu is present or absent, and when present is Ci-C5 alkylene;
X25 and X26 are selected from N and CH;
X27 is selected from N, CH, CH2, and NR25, wherein R25 is H or alky!;
R24 is selected from H, alkyl, aralkyl, aryl, and halo; and
D25 and each D26 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxy!, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000092_0001
wherein R5, Rδ, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
27. The method of claim 26, wherein the compound is
Figure imgf000092_0002
28. The method of claim 7, wherein the compound has a structure of Formula (Xl):
Figure imgf000092_0003
wherein:
X2S is selected from CH2, O, S, and NR26, wherein R26 is selected from H, alkyl, aralkyl, and aryl;
X29 is N or CH;
X30 is CH2 or NR27; wherein R27 is selected from H, alkyl, aralkyl, and aryl;
Figure imgf000092_0004
U27, D28, and D29 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000093_0001
wherein R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
29. The method of claim 28, wherein the compound is
Figure imgf000093_0002
30. The method of claim 1 , wherein the compound comprises a derivative of a parent compound having binding and/or modulation specificity for a
TrkB receptor molecule, wherein the derivative also has binding and/or modulation specificity for the TrkB receptor.
31. The method of claim 30, wherein the derivative exhibits an enhancement in at least one of the characteristics selected from the group consisting of potency, selectivity, hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound.
32. A method of facilitating neuronal or other cell survival comprising treating a neuronal or other TrkB-expressing cell with a compound having binding and/or modulation specificity for a TrkB receptor molecule.
33. The method of claim 32, wherein the compound is a mimetic of a brain-derived neurotrophic factor (BDNF) /?-tum loop.
34. The method of claim 33, wherein the compound comprises a pharmacophore substantially identical to the pharmacophore illustrated in Figure 1.
35. The method of claim 33, wherein the compound is a small molecule.
36. The method of claim 33, wherein the BDNF β-tum loop is loop 2.
37. The method of claim 36, wherein the compound has a structure of Formula (I):
R1
Figure imgf000094_0001
wherein:
R-i, R2, and R3 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
Xi and X2 are independently selected from CH2 and NR4, wherein R4 is selected from H, alkyl, aralkyl, and aryl; and Di is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000095_0001
, wherein R5 and R6 are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt.
38. The method of claim 37, wherein the compound has the structure:
Figure imgf000095_0002
or a stereoisomer thereof.
39. The method of claim 36, wherein the compound has a structure of Formula (II):
D2 L1 X3 Y1 L2 Y2 X4 L3 -D,
(H)
Zi
wherein:
Li and L3 are independently selected from the group consisting of CrC5 alkylene, arylene, aralkylene, and substituted arylene;
L2 is selected from the group consisting of C1-C-5 alkylene, arylene, aralkylene, substituted arylene,
Figure imgf000095_0003
L4 is C1-C5 alkylene; Zi, Z2, and Z3 are independently selected from the group consisting of H, alkyl, aryl, and aralkyl;
X3, X4, X5, and X6 are independently N or CH;
Yi, Y2, and Y3 are independently carbonyi, sulfonyl, or methylene; and
D2, D3, D4, and D5 are independently selected from H, alkyl, halo, hydroxyl, mercapto, mercaptoalkyl, alkoxyl, aryloxyl, aralkoxyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000096_0001
wherein R5, R6, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
40. The method of claim 39, wherein the compound is selected from the group consisting of:
Figure imgf000096_0002
Figure imgf000096_0003
Figure imgf000097_0001
41. The method of claim 36, wherein the compound has a structure of Formula (III):
Figure imgf000097_0002
wherein: l_5 is present or absent, and when present is C-i-C-s alkylene;
X7 and Xs are independently N or CH;
Rio and Rn are independently selected from the group consisting of H, halo, alkyl, and cyano;
D6, D7, and D8 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000097_0003
wherein R5, R6, R7, Rs, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
42. The method of claim 41 , wherein the compound is
Figure imgf000098_0001
43. The method of claim 36, wherein the compound has a structure of Formula (IV):
Figure imgf000098_0002
wherein:
Xg and Xio are independently CH2 or NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
Ri2 is selected from the group consisting of H, alkyl, aralkyl, aryl, acyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
R-I3 is selected from H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkycarbamoyl, and dialkylcarbamoyl;
Ri4 and R15 are independently selected from H alkyl, substituted alkyl, and aralkyl; and
R16 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000098_0003
wherein R5 and Re are H, alkyl, aralkyl, or aryl; or a pharmaceutically acceptable salt thereof.
44. The method of claim 43, wherein the compound is
Figure imgf000099_0001
or a stereoisomer thereof.
45. The method of claim 36, wherein the compound has a structure of Formula (V):
Figure imgf000099_0002
wherein: Le and L7 are independently present or absent, and when present are d-C5 alkylene;
Xn is O, S, CH2 or NRi7, wherein R17 is selected from H, alkyl, aralkyl and aryl;
Xi2, Xi3, and X14 are independently CH or N; X15 is selected from the group consisting of O, S, and NRi8, wherein R1S is selected from H, alkyl, aralkyl, and aryl; and
Dg, D10, D11, and D12 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000099_0003
; and Rs, Re, R7, Re, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
46. The method of claim 45, wherein the compound is
Figure imgf000100_0001
or a stereoisomer thereof.
47. The method of claim 36, wherein the compound has a structure of Formula (Vl):
Figure imgf000100_0002
wherein: Ls is present of absent, and when present is C1-C5 alkylene;
X16 is selected from the group consisting of O, S, and NR19, wherein R19 is selected from H, alkyl, aralkyl and aryl;
X-17 is selected from the group consisting of O, S, CH2, and NR20, wherein R2o is selected from H, alkyl, aralkyl, and aryl; Xi8 and Xig are independently selected from N and CH; and
D13 and D14 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxy), alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000101_0001
wherein R5, R6, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
48. The method of claim 47, wherein the compound is
Figure imgf000101_0002
49. The method of claim 36, wherein the compound has a structure of Formula (VII):
Figure imgf000101_0003
wherein: m and n are independently 1 or 2; each Lg and Lio can be present or absent, and when present is C1-C5 alkylene;
X20 and X21 are independently selected from CH, CH2, N, and NR4, wherein R4 is selected from H, alkyl, aralkyl and aryi;
X22 is selected from H and halo; and each D15 and each D16 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000102_0001
wherein R5, Re, Rz, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
50. The method of claim 49, wherein the compound is
Figure imgf000102_0002
51. The method of claim 36, wherein the compound has a structure of Formula (VIII):
Figure imgf000103_0001
wherein:
Lu is present or absent, and when present is C1-C5 alkylene;
X23 is N or CH;
R21 and R22 are independently selected from the group consisting of H, alkyl, aralkyl, aryl and halo; and
Di7, D18, and D19 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000103_0002
wherein R5, Re, R7, Rs, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
52. The method of claim 51 , wherein the compound is selected from the group consisting of:
Figure imgf000103_0003
Figure imgf000104_0001
53. The method of claim 36, wherein the compound has a structure of Formula (IX):
Figure imgf000104_0002
wherein:
L-12 is present or absent, and when present is C1-C5 alkylene;
X24 is N or CH;
R23 is selected from the group consisting of H, alkyl, aralkyl, aryl, and halo; and
D20, D21, D22, D23, and D23 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000105_0001
wherein R5, Re, Rz, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
54. The method of claim 53, wherein the compound is
Figure imgf000105_0002
55. The method of claim 36, wherein the compound has a structure of Formula (X):
Figure imgf000105_0003
wherein: t is 1 or 2; each Li 3 is present or absent, and when present is C1-C5 alkylene;
X25 and X26 are selected from N and CH;
X27 is selected from N, CH, CH2, and NR25, wherein R25 is H or alkyl;
R24 is selected from H, alkyl, aralkyl, aryl, and halo; and D25 and each D26 are independently selected from H, alky), aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000106_0001
wherein R5, R6, R7, Ra, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
56. The method of claim 55, wherein the compound is
Figure imgf000106_0002
57. The method of claim 36, wherein the compound has a structure of Formula (Xl):
Figure imgf000106_0003
wherein: X28 is selected from CH2, O, S, and NR26, wherein R26 is selected from H, alkyl, aralkyl, and aryl; X29 is N or CH;
X30 is CH2 or NR27; wherein R27 is selected from H, alkyl, aralkyl, and aryl;
X31 is N or CH; and
D27, D28, and D29 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000107_0001
wherein R5, R6, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof.
58. The method of claim 57, wherein the compound is
Figure imgf000107_0002
59. The method of claim 32, wherein the compound comprises a derivative of a parent compound having binding and/or modulation specificity for a TrkB receptor molecule, wherein the derivative exhibits an enhancement in at least one of the characteristics selected from the group consisting of potency, selectivity, hydrophilicity, lipophilicity, amphipathicity, solubility, bioavailability, and resistance to hepatic degradation, as compared to the parent compound.
60. The method of claim 59, wherein the derivative is selected from a derivative that has binding and/or modulation specificity for the TrkB receptor and a derivative that is transformed in vivo to have binding and/or modulation specificity for the TrkB receptor.
61. The method of claim 32, wherein the treating is done in vitro.
62. The method of claim 61 , wherein the cell is a stem cell.
63. The method of claim 62, wherein the treating further comprises one of maintaining the stem cell in an undifferentiated state and inducing differentiation in the stem cell.
64. A compound having binding and/or modulation specificity for a TrkB receptor, wherein the compound has a structure of one of Formulas (I-XI), further wherein Formula (I) has the structure:
R1
Figure imgf000108_0001
wherein:
R-I, R2, and R3 are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl; Xi and X2 are independently selected from CH2 and NR4, wherein R4 is selected from H, alkyl, aralkyl, and aryl; and
Di is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000109_0001
, wherein R5 and RQ are H, alkyl, aralkyl, or aryl;
Formula (II) has the structure:
D2 L1 X3 Y1 L2 Y2 X4 L3 D3 /m
I I
Z1 Z2 wherein: Li and L3 are independently selected from the group consisting of C1-C5 alkylene, arylene, aralkylene, and substituted arylene;
L2 is selected from the group consisting of C1-C5 alkylene, arylene, aralkylene, substituted arylene,
Figure imgf000109_0002
L4 is C1-C5 alkylene;
Zi, Z2, and Z3 are independently selected from the group consisting of H, alkyl, aryl, and aralkyl;
X3, X4, X5, and Xe are independently N or CH; Yi, Y2, and Y3 are independently carbonyl, sulfonyl, or methylene; and
D2, D3, D4, and D5 are independently selected from H, alkyl, halo, hydroxyl, mercapto, mercaptoalkyl, alkoxyl, aryloxyl, aralkoxyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000110_0001
wherein R5, R6, Rγ, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; Formula (III) has the structure:
Figure imgf000110_0002
wherein:
L5 is. present or absent, and when present is CrC5 alkylene;
X7 and X8 are independently N or CH;
Rio and Rn are independently selected from the group consisting of H, halo, alkyl, and cyano;
D6, D7, and D8 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000110_0003
wherein R5, R6, R7, R8, and Rg are independently selected from H, alkyl, aralkyl, and aryl; Formula (IV) has the structure:
Figure imgf000111_0001
wherein:
X9 and X10 are independently CH2 or NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
R12 is selected from the group consisting of H, alkyl, aralkyl, aryl, acyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl;
R-13 is selected from H, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamoyl, alkycarbamoyl, and dialkylcarbamoyl;
Ri4 and R15 are independently selected from H alkyl, substituted alkyl, and aralkyl; and
R16 is selected from the group consisting of H, alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, and
Figure imgf000111_0002
wherein R5 and R6 are H, alkyl, aralkyl, or aryl; Formula (V) has the structure:
Figure imgf000111_0003
wherein:
Le and L7 are independently present or absent, and when present are C-1-C5 alkylene;
X11 is O, S, CH2 or NR17, wherein R17 is selected from H, alkyl, aralkyl and aryl;
X12, X^, and X14 are independently CH or N; Xi5 is selected from the group consisting of O, S, and NRi8, wherein Ris is selected from H, alkyl, aralkyl, and aryl; and
Dg, Dio, Dii, and Di2 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, acyloxyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000112_0001
Rs, Rδ, R7, Re, and R9 are independently selected from H, alkyl, aralkyl, and aryl;
Formula (Vl) has the structure:
Figure imgf000112_0002
wherein:
Le is present or absent, and when present is CrC5 alkylene; X16 is selected from the group consisting of O, S, and NR19, wherein R19 is selected from H, alkyl, aralkyl and aryl;
Xi7 is selected from the group consisting of O, S, CH2, and NR20, wherein R20 is selected from H, alkyl, aralkyl, and aryl;
Xis and X19 are independently selected from N and CH; and Di3 and D14 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000113_0001
wherein R5, R&, R7, R8, and Rg are independently selected from H, alkyl, aralkyl, and aryl; Formula (VII) has the structure:
Figure imgf000113_0002
wherein: m and n are independently 1 or 2; each L9 and Li0 can be present or absent, and when present is C-1-C5 alkylene;
X20 and X21 are independently selected from CH, CH2, N, and NR4, wherein R4 is selected from H, alkyl, aralkyl and aryl;
X22 is selected from H and halo; and each D15 and each D16 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000113_0003
wherein R5, RQ, R7, R8, and R9 are independently selected from H, alkyl, aralkyl, and aryl; Formula (VIII) has the structure:
Figure imgf000114_0001
wherein:
Li 1 is present or absent, and when present is C1-C5 alkylene;
X23 is N or CH;
R21 and R22 are independently selected from the group consisting of H, alkyl, aralkyl, aryl and halo; and
Di7, Die, and D19 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000114_0002
wherein Rs, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; Formula (IX) has the structure:
wherein:
L|2 is present or absent, and when present is C1-C5 alkylene;
X24 is N or CH;
R23 is selected from the group consisting of H, alkyl, aralkyl, aryl, and halo; and D2O, D2i, D22, D23, and D23 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000115_0001
wherein R5, Re, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; Formula (X) has the structure:
Figure imgf000115_0002
wherein: t is 1 or 2; each L13 is present or absent, and when present is CrC5 alkylene;
X25 and X26 are selected from N and CH;
X27 is selected from N, CH, CH2, and NR25, wherein R25 is H or alkyl;
R24 is selected from H, alkyl, aralkyl, aryl, and halo; and
D25 and each D26 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000116_0001
wherein R5, R6, R7, Rs, and Rg are independently selected from H, alkyl, aralkyl, and aryl; and Formula (Xl) has the structure:
Figure imgf000116_0002
wherein:
X28 is selected from CH2, O, S, and NR26, wherein R26 is selected from H, alkyl, aralkyl, and aryl;
X29 is N or CH;
X30 is CH2 or NR27; wherein R27 is selected from H, alkyl, aralkyl, and aryl;
X31 is N or CH; and
D27, D28, and D29 are independently selected from H, alkyl, aryl, aralkyl, halo, hydroxyl, alkoxyl, aralkoxyl, aryloxyl, mercapto, mercaptoalkyl, carboxyl, acyloxyl, alkyloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
Figure imgf000116_0003
wherein R5, R6, R7. Rs, and R9 are independently selected from H, alkyl, aralkyl, and aryl; or a pharmaceutically acceptable salt thereof, with the proviso that the compound of Formula (I-XI) is not a compound selected from the group consisting of:
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000118_0001
Figure imgf000119_0001
65. A method of coating a substrate for use in an environment where a TrkB receptor is present, the method comprising coating the substrate with with a composition comprising a molecule having binding and/or modulation specificity for a TrkB receptor.
66. A method of imaging a cell having a TrkB receptor, the method comprising:
(a) contacting the cell with a compound having a binding and/or modulation specificity for a TrkB receptor, the compound further comprising a detectable label; and (b) detecting the detectable label, thereby imaging the cell.
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