WO2002070011A2 - Treatment of ppar mediated diseases - Google Patents

Treatment of ppar mediated diseases Download PDF

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Publication number
WO2002070011A2
WO2002070011A2 PCT/US2002/003017 US0203017W WO02070011A2 WO 2002070011 A2 WO2002070011 A2 WO 2002070011A2 US 0203017 W US0203017 W US 0203017W WO 02070011 A2 WO02070011 A2 WO 02070011A2
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Prior art keywords
ppar
treatment
expression
abca1
activity
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PCT/US2002/003017
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French (fr)
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WO2002070011A3 (en
Inventor
Timothy Mark Willson
Jennifer L. FOX
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Smithkline Beecham Corporation
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Priority to US10/470,886 priority Critical patent/US20040138094A1/en
Priority to AU2002243778A priority patent/AU2002243778A1/en
Priority to EP02709285A priority patent/EP1357914A2/en
Publication of WO2002070011A2 publication Critical patent/WO2002070011A2/en
Publication of WO2002070011A3 publication Critical patent/WO2002070011A3/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1783—Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70567—Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention is in the field of pharmacology and medicine. More particularly this invention relates to methods of identifying suitable treatment regimes for diseases or conditions mediated by Peroxisome Proliferator- Activated Receptors (PPARs), particularly those mediated by PPAR delta. In another aspect the invention provides a method of promoting reverse cholesterol transport in an individual.
  • PPARs Peroxisome Proliferator- Activated Receptors
  • lipid homestasis is a delicate balance between dietary intake, de novo synthesis and catabolism.
  • the increased incidence of cardiovascular disease in Westernized countries has been linked to dyslipidemias associated with changes in the fat content of the diet (1).
  • Obesity, insulin resistance and hypertension are comorbidities with these lipid disorders, which together are known as the metabolic syndrome X (2).
  • Individuals with this condition have raised serum triglycerides and abnormally low levels of high density lipoprotein cholesterol (HDLc) (2, 3).
  • HDLc high density lipoprotein cholesterol
  • HDL plays a protective role through the process of "reverse cholesterol transport" whereby cholesterol is removed from peripheral cells, including the macrophage-derived foam cells, and returned to the liver (5).
  • Agents that raise the levels of HDL by stimulating reverse cholesterol transport would provide a new therapeutic option for the prevention of atherosclerotic cardiovascular disease (6).
  • ABC1 ATP-binding cassette A1
  • Fibrates are a class of drugs that have been used for decades for their beneficial effects on serum lipids. Although fibrates are predominantly triglyceride-lowering drugs that only modestly raise HDLc (12, 13), clinical trials have shown that they lower the incidence of atherosclerosis and coronary artery disease in patients with normal levels of LDLc (12, 14). Most fibrate drugs are only weakly active on human PPAR and show low selectivity over human PPAR ⁇ and PPAR ⁇ (15).
  • PPAR ⁇ increases cholesterol efflux from cells through an increase in the expression of the ABCA1 cholesterol and phospholipid transporter.
  • ABCA1 cholesterol and phospholipid transporter These data and its broad tissue distribution suggest that PPAR ⁇ is an important regulator of reverse cholesterol transport in mammals, and thus has unique pharmacology that distinguishes it from the other PPAR subtypes.
  • PPAR ⁇ modulators may therefore provide a new approach to the treatment of cardiovascular disease by promoting reverse cholesterol transport, an effect not previously associated with PPAR delta. It would be desirable to test the effectiveness of drugs for PPAR delta mediated diseases or conditions. Measuring blood HDLc levels may indicate HDLc is increased but will not indicate the mechanism by which this occurs and thus whether the HDLc increase is clinically beneficial.
  • ABCA1 may be used as a surrogate marker for measuring activity of PPAR delta and therefore indicating the level of reverse cholesterol transport as well as increase in HDLc. This would provide a more objective standard and a test by which a drug could be tested for its effectiveness in individuals.
  • the present invention provides a method of increasing ABCA1 activity and/or expression and promoting reverse cholesterol transport in a subject, comprising administering to the subject a therapeutically effective amount of an modulator of PPAR delta.
  • the present invention provides the use of a PPAR delta modulator for the manufacture of a medicament for the purpose of increasing ABCA1 activity and/or expression and promoting reverse cholesterol transport in a subject.
  • This invention also provides a method for testing a compound or composition for the treatment of a PPAR mediated disease or condition.
  • the method comprises administering a PPAR delta modulator against one or more subjects and determining the level of ABCA1 expression and/or activity.
  • This method is also useful in determining the level of efficacy of a treatment with a PPAR delta modulator, depending upon the extent to which the treatment can cause ABCA1 expression and/or activity.
  • the present invention extends to the use of a compound or composition identified by this method in the manufacture of a medicament for the treatment of PPAR mediated diseases or conditions in a patient in need thereof and a method of treatment of PPAR mediated diseases or conditions which comprises the administration of a therapeutically effective amount of a compound identified by the above method to a patient in need thereof.
  • the invention also provides a method for identifying a suitable treatment regime for treating a PPAR mediated disease or condition in an individual. The method involves determining a regime for a compound or composition which increases ABCA1 expression and/or activity comprising administering a compound, measuring ABCA1 expression and/or activity whereby the determined regime provides an effective treatment.
  • Fig. 1 Regulation of ABCA1 expression and cholesterol efflux from THP1 macrophages. Compounds were used at the following concentrations: PPAR ⁇ (GW501516), 100 nM; PPAR ⁇ (GW7647), 100 nM; PPAR ⁇ (GW7845), 100 nM. Data are presented as the mean of assays performed in triplicate ⁇ S. D A. ABCA1 mRNA levels determined by RTQ-PCR. ⁇ . ApoA1 -specific cholesterol efflux.
  • hPPAR mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa.
  • Particular diseases include diabetes and cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia
  • the methods of this invention employing ABCA1 as a surrogate marker can be used at any stage, including during clinical trial or after approval of a pharmaceutical product by the appropriate regulatory authority (e.g. the United States Food and Drug Administration).
  • the pharmaceutical product comprises a PPAR delta modulator that is not known for effectiveness in PPAR mediated diseases or that has not been approved for use in PPAR mediated diseases.
  • PPAR delta modulating compounds or compositions that already have been approved can be tested according to the invention also.
  • the treatment regime can include any factors relating to the treatment, including, without limitation, the identity of the drug or drugs administered, the amount administered, the timing of delivery, if the regime involves a combination of one or more drugs, the ratio of drugs in combination and their interaction, the route of delivery, and the pharmaceutical formulation employed.
  • the method can be performed on groups of individuals or on a single individual. Performing the method on a single individual, especially one who suffers from a PPAR mediated disease or condition, is useful in order to determine a customised treatment for protocol for the individual. Groups of individuals are useful in order to obtain data for statistical analysis in order to identify treatment protocols for a population in general.
  • the groups of individuals can be individuals who suffer from a PPAR mediated disease or condition or alternatively, because the methods use surrogate markers, the subjects can be persons who do not suffer from a PPAR mediated disease or condition.
  • the number of persons in a study is at the discretion of the researcher, who normally will use standard protocols for obtaining statistically significant results.
  • the protocol can be supplied as a label on a package containing the drug and the protocol can be administered to a patient.
  • composition refers to a composition of at least one drug to be tested. Accordingly, the composition can be a mixture of more than one drug provided in various ratios.
  • the composition generally will be administered in the form of a composition comprising at least two drugs in a particular ratio.
  • the invention involves testing different ratios of various drugs to identify ratios that cause an inhibition of a reflux inhibition of a surrogate market. Alternatively, drugs can be administered separately in different timing schedules.
  • the drugs tested generally will be PPAR delta modulators. Other agents, which may not themselves display efficacy but which potentiate the effacy of other agents may also be used.
  • the drugs are hPPAR ⁇ agonists.
  • agonist or “activating compound”, or “activator”, or the like, is meant those compounds which have a pKi of at least 6.0, preferably at least 7.0, to the relevant PPAR, for example hPPAR ⁇ in the binding assay described in WO01/00603, and which achieve at least 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the transfection assay described at concentrations of 10 "5 M or less.
  • the agonist of this invention achieve 50% activation of human PPAR ⁇ in the transfection assay at concentrations of 10 "7 M or less, more preferably 10 "9 M or less.
  • the drugs are selective hPPAR ⁇ agonists.
  • a "selective hPPAR ⁇ agonist” is a hPPAR ⁇ agonist whose EC50 for PPAR ⁇ is at least 10 fold lower than its EC50 for PPAR ⁇ and PPAR ⁇ .
  • Such selective compounds may be referred to as "10-fold selective.”
  • EC50 is defined in the transfection assay described in WO01/00603 and is the concentration at which a compound achieves 50% of its maximum activity. Most pr -ferred compounds are greater than 100-fold selective hPPAR ⁇ agonists.
  • the therapeutic protocol is tested as a function of its ability to cause PPAR delta activation. Because there is no simple way to directly measure PPAR delta agonist activity, this invention relies on the use of ABCA1 as a surrogate marker.
  • a "surrogate marker" for activity of PPAR delta is a marker that indicates increased or decreased activity of PPAR delta.
  • ABCA1 activity is easy to measure, ABCA1 expression and/or activity is a preferred surrogate marker for this invention. This can be measured under many different conditions. These include, e.g., ABCAI mRNA levels in blood or tissues using Taq Man, Quantigene or Northern blot. ABCA1 protein levels could be measured by using a specific antibody and ELISA.
  • Effectiveness of the treatment generally will coincide with the time ABCA1 expression and/or activity occurs, indicating reverse cholesterol transport. Therefore, it is useful to test for activity over the course of minutes or hours after administration of the drug. However, detecting increased ABCA1 expression and/or activity at any time after administration of the drug is a positive indication of efficacy.
  • a certain amount of a drug usually is necessary to obtain any pharmacological effect. Overdoses of a drug can have harmful side effects. Similarly, because it effects bioavailability, among other things, routes of administration also effect efficacy. Thus, this invention contemplates determining the effect of dose or route of administration, alone or together, as part of determining a ABCA1 activity formulation and dosing regime.
  • the dose administered will be a dose within a range determined to be safe.
  • dosage amounts will be between about 0.02-5000mg per day.
  • composition can be formulated for administration in a variety of ways.
  • Typical routes of administration include both enteral and parenteral. These include, without limitation, subcutaneous, intramuscular, intravenous, intraperitoneal, intramedullary, intrapericardiac, intrabursal, oral, sublingual, ocular, nasal, topical, transdermal, transmucosal, or anal.
  • the mode of administration can be, eg. via swallowing, inhalation, injection or topical application to a surface (e.g., eyes, mucus membrane, skin).
  • the formulation can be in any of the usual forms, including aqueous solution, for enteral, parenteral or transmucosal administration, e.g., for intravenous administration, as liquid formulations and administration to mucus or other membranes as, for example, nose (nasal) or eye drops; solid and other non-aqueous compositions for enteral or transdermal delivery e.g., as pills, tablets, powders, ointments, suppositories or capsules; transdermal, transmucosal or rectal delivery systems for topical administration, and aerosols or mists for delivery by inhalation.
  • aqueous solution for enteral, parenteral or transmucosal administration, e.g., for intravenous administration, as liquid formulations and administration to mucus or other membranes as, for example, nose (nasal) or eye drops
  • solid and other non-aqueous compositions for enteral or transdermal delivery e.g., as pills, tablets,
  • Another parameter of the treatment regime can be timing of administration, e.g., time between doses, timed release of doses, etc.
  • Testing may indicate that treatment regime results in no change in the surrogate marker, an inhibition of the marker or a stimulation of the marker. Those that cause, increase in activity of the surrogate marker within a safe range indicate useful protocols for delivery of the drug for therapeutic treatment.
  • This invention allows one to determine level of efficacy of a treatment.
  • Compounds known to be effective in the treatment of PPAR mediated diseases can be tested to determine the level of ABCA1 activity and a standard set up relating amount of ABCA1 activity with amount of efficacy. Then, a ' composition can be tested in a treatment regime and the level of ABCA1 activity measured. This level is then compared with the standard curve to determine the expected level of efficacy.
  • THP1 human monocyte cells (ATCC TID-202), in 6-well plates at a density of 1 x 10 6 cells/well in RPMI 1640 medium containing 10% FBS, were differentiated into macrophages by treatment with PMA (100 ng/ml) for 5 days.
  • PMA 100 ng/ml
  • Total RNA was generated using the Qiagen RNeasy Mini Kit and DNase treated according to the manufacturer's protocol (Ambion).
  • ABCA1 expression was analysed using RTQ- PCR on an ABI PRISM 7700 sequence detection system (P. E. Applied Biosystems). Primer/probe sequences used were as follows: ABCA1 forward primer ⁇ '-TGTCCAGTCCAGTAATGGTTCTGTGT-S' , (Seq ID No:1 ) reverse primer 5'-GCGAGATATGGTCCGGATTG-3 ⁇ (Seq ID No:2) probe 5'FAM- ACACCTGGAGAGAAGCTTTCAACGAGACTAACC-TAMRA3'( Seq ID No:3) Expression data were normalised to 18S as described by the vendor.
  • THP1 cells were washed in serum-free medium and incubated in 5% FBS medium containing 1 ⁇ Ci/mL of [ 3 H]- cholesterol (New England Nuclear) and 0.2% fatty acid-free BSA (faf BSA) for a further 24 h.
  • the cells were washed in serum-free medium and then incubated for 24 h in serum-free medium supplemented with 1.5% faf BSA ⁇ test compound or vehicle (0.1 % DMSO). The equilibration medium was removed and the cells washed twice in serum-free medium.
  • Serum-free DMEM containing compound ⁇ purified human apolipoprotein (apo) Al (10 mg/ml, Athens Research & Technology) was added. The cells were maintained for 24 h before medium and cell extract samples were generated. Scintillation counting was performed to determine the percentage cellular cholesterol efflux ⁇ apoAI.
  • 1 BR3N human skin fibroblast cells were plated in 6-well plates at a density of 1 x 10? cells/well in DMEM medium containing 10% FBS and cultured for 24 h. Efflux studies were performed as in the THP1 macrophages except that the cells were maintained for 48 h before scintillation counting was performed.
  • THP1 macrophages were dosed with ligands selective for each of the three subtypes.
  • the PPAR ⁇ agonist GW501516 showed strong induction of ABCA1 mRNA expression (Fig. 1A).
  • the PPAR ⁇ agonist GW7845 also induced ABCA1 expression, while the PPAR ⁇ agonist GW7647 showed only a weak effect.
  • the PPAR ⁇ agonist GW501516 produced a 2-fold increase in cholesterol efflux to apoAI (Fig. 1B and Table 1).
  • PPAR ⁇ regulates cholesterol efflux from macrophages.
  • both the PPAR ⁇ and PPAR ⁇ agonists were ineffective, despite their ability to produce small increases in ABCA1 expression in these cells.
  • Percent increase was calculated from (GW-vehicle) ⁇ tehicle x 100. Data are presented as the mean of assays performed in triplicate ⁇ S. D. N. D., not determined.
  • PPAR ⁇ is expressed in many tissues that contribute to cholesterol flux (22).
  • GW501516 in human fibroblast and intestinal cell lines (Table 1).
  • 1BR3N human skin fibroblasts the selective PPAR ⁇ agonist produced a 3.4-fold increase in ABCA1 expression and a 2-fold increase in apoA1 -specific cholesterol efflux.
  • FHS74 human intestinal cells 23
  • the selective PPAR ⁇ agonist produced a 2.1 -fold increase in ABCA1 expression.

Abstract

This invention provides a method for identifying a treatment regime for a compound or composition effective in treating a PPAR mediated disease or condition. The method includes determingin a treatment regime for the compound or composition that causes expression of a surrogate market for PPAR delta activity whereby the determined dose and route of administration identifies an effective treatment protocol.

Description

Treatment Regimes
Field of the Invention
The present invention is in the field of pharmacology and medicine. More particularly this invention relates to methods of identifying suitable treatment regimes for diseases or conditions mediated by Peroxisome Proliferator- Activated Receptors (PPARs), particularly those mediated by PPAR delta. In another aspect the invention provides a method of promoting reverse cholesterol transport in an individual.
Background of the Invention
In humans, lipid homestasis is a delicate balance between dietary intake, de novo synthesis and catabolism. The increased incidence of cardiovascular disease in Westernized nations has been linked to dyslipidemias associated with changes in the fat content of the diet (1). Obesity, insulin resistance and hypertension are comorbidities with these lipid disorders, which together are known as the metabolic syndrome X (2). Individuals with this condition have raised serum triglycerides and abnormally low levels of high density lipoprotein cholesterol (HDLc) (2, 3). This lipid profile is accompanied by an increase in the proportion of small-dense low density lipoprotein particles, which are prone to accumulate in the arterial wall leading to the formation of atherosclerotic cholesterol-laden foam cells (4). HDL plays a protective role through the process of "reverse cholesterol transport" whereby cholesterol is removed from peripheral cells, including the macrophage-derived foam cells, and returned to the liver (5). Agents that raise the levels of HDL by stimulating reverse cholesterol transport would provide a new therapeutic option for the prevention of atherosclerotic cardiovascular disease (6).
Recently, the ATP-binding cassette A1 (ABCA1) protein has been identified as a regulator of cholesterol and phospholipid transport from cells (7). Patients with Tangier disease or familial hypoalphalipoproteinia have been identified with loss of function mutations in the ABCA1 gene (8-10). These patients have low levels of HDLc and high triglycerides and show an increased incidence of cardiovascular disease (11). Thus, therapies that increase the expression of ABCA1 could provide a new approach to treating atherogenic dyslipidemia (5).
Fibrates are a class of drugs that have been used for decades for their beneficial effects on serum lipids. Although fibrates are predominantly triglyceride-lowering drugs that only modestly raise HDLc (12, 13), clinical trials have shown that they lower the incidence of atherosclerosis and coronary artery disease in patients with normal levels of LDLc (12, 14). Most fibrate drugs are only weakly active on human PPAR and show low selectivity over human PPARδ and PPARγ (15).
It was recently reported that the experimental fibrate drug Wy14,643 induces ABCA1 expression and cholesterol efflux from macrophages (16). However, at the concentrations employed in the study (50 μM), Wy 14,643 has significant PPARδ activity [EC50 = 35 μM for human PPARδ (15)]. Using compounds that are selective for each of the three PPAR subtypes, we have now shown that their relative ability to induce ABCA1 expression is PPARδ > PPARγ > PPARα. These data argue that the reported effects (16) of high doses of fibrates on cholesterol efflux are mediated primarily through PPARδ.
Compounds that agonise the function of human PPAR delta have been described in WO 01/00603 and have been shown to increase HDLc
The present inventors have now provided evidence that PPARδ increases cholesterol efflux from cells through an increase in the expression of the ABCA1 cholesterol and phospholipid transporter. These data and its broad tissue distribution suggest that PPARδ is an important regulator of reverse cholesterol transport in mammals, and thus has unique pharmacology that distinguishes it from the other PPAR subtypes. PPARδ modulators may therefore provide a new approach to the treatment of cardiovascular disease by promoting reverse cholesterol transport, an effect not previously associated with PPAR delta. It would be desirable to test the effectiveness of drugs for PPAR delta mediated diseases or conditions. Measuring blood HDLc levels may indicate HDLc is increased but will not indicate the mechanism by which this occurs and thus whether the HDLc increase is clinically beneficial. Thus ABCA1 may be used as a surrogate marker for measuring activity of PPAR delta and therefore indicating the level of reverse cholesterol transport as well as increase in HDLc. This would provide a more objective standard and a test by which a drug could be tested for its effectiveness in individuals.
Summary of the Invention
Accordingly the present invention provides a method of increasing ABCA1 activity and/or expression and promoting reverse cholesterol transport in a subject, comprising administering to the subject a therapeutically effective amount of an modulator of PPAR delta.
In a further aspect, the present invention provides the use of a PPAR delta modulator for the manufacture of a medicament for the purpose of increasing ABCA1 activity and/or expression and promoting reverse cholesterol transport in a subject.
This invention also provides a method for testing a compound or composition for the treatment of a PPAR mediated disease or condition. The method comprises administering a PPAR delta modulator against one or more subjects and determining the level of ABCA1 expression and/or activity. This method is also useful in determining the level of efficacy of a treatment with a PPAR delta modulator, depending upon the extent to which the treatment can cause ABCA1 expression and/or activity. The present invention extends to the use of a compound or composition identified by this method in the manufacture of a medicament for the treatment of PPAR mediated diseases or conditions in a patient in need thereof and a method of treatment of PPAR mediated diseases or conditions which comprises the administration of a therapeutically effective amount of a compound identified by the above method to a patient in need thereof. In a further aspect, the invention also provides a method for identifying a suitable treatment regime for treating a PPAR mediated disease or condition in an individual. The method involves determining a regime for a compound or composition which increases ABCA1 expression and/or activity comprising administering a compound, measuring ABCA1 expression and/or activity whereby the determined regime provides an effective treatment.
Description of the Drawings
Fig. 1. Regulation of ABCA1 expression and cholesterol efflux from THP1 macrophages. Compounds were used at the following concentrations: PPARδ (GW501516), 100 nM; PPARα (GW7647), 100 nM; PPARγ (GW7845), 100 nM. Data are presented as the mean of assays performed in triplicate ± S. D A. ABCA1 mRNA levels determined by RTQ-PCR. β. ApoA1 -specific cholesterol efflux.
Detailed Description of the Invention
Measuring ABCA1 activity as a surrogate marker for PPAR delta activity is useful for identifying effective treatment regimes for individuals suffering from or pre disposed to diseases or conditions mediated by PPARs. hPPAR mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. Particular diseases include diabetes and cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia, The methods of this invention employing ABCA1 as a surrogate marker can be used at any stage, including during clinical trial or after approval of a pharmaceutical product by the appropriate regulatory authority (e.g. the United States Food and Drug Administration). In one embodiment, the pharmaceutical product comprises a PPAR delta modulator that is not known for effectiveness in PPAR mediated diseases or that has not been approved for use in PPAR mediated diseases. However, PPAR delta modulating compounds or compositions that already have been approved can be tested according to the invention also.
The treatment regime can include any factors relating to the treatment, including, without limitation, the identity of the drug or drugs administered, the amount administered, the timing of delivery, if the regime involves a combination of one or more drugs, the ratio of drugs in combination and their interaction, the route of delivery, and the pharmaceutical formulation employed.
The method can be performed on groups of individuals or on a single individual. Performing the method on a single individual, especially one who suffers from a PPAR mediated disease or condition, is useful in order to determine a customised treatment for protocol for the individual. Groups of individuals are useful in order to obtain data for statistical analysis in order to identify treatment protocols for a population in general. The groups of individuals can be individuals who suffer from a PPAR mediated disease or condition or alternatively, because the methods use surrogate markers, the subjects can be persons who do not suffer from a PPAR mediated disease or condition. The number of persons in a study is at the discretion of the researcher, who normally will use standard protocols for obtaining statistically significant results. Upon determining that a drug or drug combination causes expression and/or activation of ABCA1 , the protocol can be supplied as a label on a package containing the drug and the protocol can be administered to a patient.
"Composition" refers to a composition of at least one drug to be tested. Accordingly, the composition can be a mixture of more than one drug provided in various ratios. The composition generally will be administered in the form of a composition comprising at least two drugs in a particular ratio. In one embodiment, the invention involves testing different ratios of various drugs to identify ratios that cause an inhibition of a reflux inhibition of a surrogate market. Alternatively, drugs can be administered separately in different timing schedules.
The drugs tested generally will be PPAR delta modulators. Other agents, which may not themselves display efficacy but which potentiate the effacy of other agents may also be used. Preferably, the drugs are hPPARδ agonists. As used herein, by "agonist", or "activating compound", or "activator", or the like, is meant those compounds which have a pKi of at least 6.0, preferably at least 7.0, to the relevant PPAR, for example hPPARδ in the binding assay described in WO01/00603, and which achieve at least 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the transfection assay described at concentrations of 10"5 M or less. Preferably, the agonist of this invention achieve 50% activation of human PPARδ in the transfection assay at concentrations of 10"7 M or less, more preferably 10"9M or less.
Most preferably, the drugs are selective hPPARδ agonists. As used herein, a "selective hPPARδ agonist" is a hPPARδ agonist whose EC50 for PPARδ is at least 10 fold lower than its EC50 for PPARγ and PPARα. Such selective compounds may be referred to as "10-fold selective." EC50 is defined in the transfection assay described in WO01/00603 and is the concentration at which a compound achieves 50% of its maximum activity. Most pr -ferred compounds are greater than 100-fold selective hPPARδ agonists.
According to the method of this invention, the therapeutic protocol is tested as a function of its ability to cause PPAR delta activation. Because there is no simple way to directly measure PPAR delta agonist activity, this invention relies on the use of ABCA1 as a surrogate marker. A "surrogate marker" for activity of PPAR delta is a marker that indicates increased or decreased activity of PPAR delta.
ABCA1 activity is easy to measure, ABCA1 expression and/or activity is a preferred surrogate marker for this invention. This can be measured under many different conditions. These include, e.g., ABCAI mRNA levels in blood or tissues using Taq Man, Quantigene or Northern blot. ABCA1 protein levels could be measured by using a specific antibody and ELISA.
Effectiveness of the treatment generally will coincide with the time ABCA1 expression and/or activity occurs, indicating reverse cholesterol transport. Therefore, it is useful to test for activity over the course of minutes or hours after administration of the drug. However, detecting increased ABCA1 expression and/or activity at any time after administration of the drug is a positive indication of efficacy.
Two important factors that can effect efficacy of a drug are dose and route of administration. For example, a certain amount of a drug usually is necessary to obtain any pharmacological effect. Overdoses of a drug can have harmful side effects. Similarly, because it effects bioavailability, among other things, routes of administration also effect efficacy. Thus, this invention contemplates determining the effect of dose or route of administration, alone or together, as part of determining a ABCA1 activity formulation and dosing regime.
The dose administered will be a dose within a range determined to be safe. For example, dosage amounts will be between about 0.02-5000mg per day.
The composition can be formulated for administration in a variety of ways. Typical routes of administration include both enteral and parenteral. These include, without limitation, subcutaneous, intramuscular, intravenous, intraperitoneal, intramedullary, intrapericardiac, intrabursal, oral, sublingual, ocular, nasal, topical, transdermal, transmucosal, or anal. The mode of administration can be, eg. via swallowing, inhalation, injection or topical application to a surface (e.g., eyes, mucus membrane, skin). The formulation can be in any of the usual forms, including aqueous solution, for enteral, parenteral or transmucosal administration, e.g., for intravenous administration, as liquid formulations and administration to mucus or other membranes as, for example, nose (nasal) or eye drops; solid and other non-aqueous compositions for enteral or transdermal delivery e.g., as pills, tablets, powders, ointments, suppositories or capsules; transdermal, transmucosal or rectal delivery systems for topical administration, and aerosols or mists for delivery by inhalation.
Another parameter of the treatment regime can be timing of administration, e.g., time between doses, timed release of doses, etc.
Testing may indicate that treatment regime results in no change in the surrogate marker, an inhibition of the marker or a stimulation of the marker. Those that cause, increase in activity of the surrogate marker within a safe range indicate useful protocols for delivery of the drug for therapeutic treatment.
This invention allows one to determine level of efficacy of a treatment. Compounds known to be effective in the treatment of PPAR mediated diseases can be tested to determine the level of ABCA1 activity and a standard set up relating amount of ABCA1 activity with amount of efficacy. Then, a' composition can be tested in a treatment regime and the level of ABCA1 activity measured. This level is then compared with the standard curve to determine the expected level of efficacy.
EXAMPLES
The invention will now be illustrated by reference to the following examples which should not be construed as a limitation thereto.
Cell Culture and ABCA1 expression
THP1 human monocyte cells (ATCC TID-202), in 6-well plates at a density of 1 x 106 cells/well in RPMI 1640 medium containing 10% FBS, were differentiated into macrophages by treatment with PMA (100 ng/ml) for 5 days. 1 BR3N human skin fibroblasts (ECACC 90020508) and FHS74 human intestinal cells (ATCC CCL-241) were plated in 6 well plates at a density of 1 x 106 cells/well in the recommended maintenance media. Cells were treated with vehicle (0.1% DMSO) or test compound for 48 h prior to harvesting. Total RNA was generated using the Qiagen RNeasy Mini Kit and DNase treated according to the manufacturer's protocol (Ambion). ABCA1 expression was analysed using RTQ- PCR on an ABI PRISM 7700 sequence detection system (P. E. Applied Biosystems). Primer/probe sequences used were as follows: ABCA1 forward primer δ'-TGTCCAGTCCAGTAATGGTTCTGTGT-S' , (Seq ID No:1 ) reverse primer 5'-GCGAGATATGGTCCGGATTG-3\ (Seq ID No:2) probe 5'FAM- ACACCTGGAGAGAAGCTTTCAACGAGACTAACC-TAMRA3'( Seq ID No:3) Expression data were normalised to 18S as described by the vendor.
Cholesterol efflux studies
Following differentiation to macrophages, THP1 cells were washed in serum-free medium and incubated in 5% FBS medium containing 1 μCi/mL of [3H]- cholesterol (New England Nuclear) and 0.2% fatty acid-free BSA (faf BSA) for a further 24 h. The cells were washed in serum-free medium and then incubated for 24 h in serum-free medium supplemented with 1.5% faf BSA ± test compound or vehicle (0.1 % DMSO). The equilibration medium was removed and the cells washed twice in serum-free medium. Serum-free DMEM containing compound ± purified human apolipoprotein (apo) Al (10 mg/ml, Athens Research & Technology) was added. The cells were maintained for 24 h before medium and cell extract samples were generated. Scintillation counting was performed to determine the percentage cellular cholesterol efflux ± apoAI. 1 BR3N human skin fibroblast cells were plated in 6-well plates at a density of 1 x 10? cells/well in DMEM medium containing 10% FBS and cultured for 24 h. Efflux studies were performed as in the THP1 macrophages except that the cells were maintained for 48 h before scintillation counting was performed.
Example 1
Recently, several nuclear receptors that form heterodimers with RXR have been evaluated for their ability to regulate expression of the cholesterol transporter ABCA1. Repa, J. J., Turley, S. D., Lobaccaro, J. M. A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R. A., Dietschy, J. M. & Mangelsdorf, D. J. (2000) Science 289, 1524-1529) for either RXR or the liver X receptor α (LXRα) induce ABCA1 expression in murine peritoneal macrophages, human primary macrophages or THP1 macrophages (Repa, J. J., Turley, S. D., Lobaccaro, J. M. A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R. A., Dietschy, J. M. & Mangelsdorf, D. J. (2000) Science 289, 1524-1529. Venkateswaran, A., Laffitte, B. A., Joseph, S. B., Mak, P. A., Wilpitz, D. C, Edwards, P. A. & Tontonoz, P. (2000) Proc. Natl. Acad. Sci. USA 97, 12097-12102. Costet, P., Luo, Y., Wang, N. & Tall, A. R. (2000) J. Biol. Chem. 275, 28240-28245).
To assess the potential for the PPARs to regulate this process, THP1 macrophages were dosed with ligands selective for each of the three subtypes. At 100 nM, GW7647 (Willson T. M et al (2000) J. Med. Chem. 43 527-550, Brown P.J. et al (1997) Chem Bio. 4, 909-918) is a selective PPARα agonist (EC50 = 6, 1070, and 6200 nM on human PPARα, PPARγ, and PPARδ, respectively), GW7845 (Willson T.M. et al (2000) J. Med. Chem. 43 527-550, Cobb, J.E. et al (1998) J. Med Chem 4 5055-5069) is a selective PPARγ agonist (EC50 = 3500, 0.7, and >10000 nM on human PPARα, PPARγ, and PPARδ respectively), and GW501516 (2-(2-methyl-4[({4-methyl-2[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
WO01/00603) is a selective PPARδ agonist (EC50 = 1400, 1200, and 1.2 nM on human PPARα, PPARγ, and PPARδ, respectively). The PPARδ agonist GW501516 showed strong induction of ABCA1 mRNA expression (Fig. 1A). The PPARγ agonist GW7845 also induced ABCA1 expression, while the PPARα agonist GW7647 showed only a weak effect. The PPARδ agonist GW501516 produced a 2-fold increase in cholesterol efflux to apoAI (Fig. 1B and Table 1). Thus, PPARδ regulates cholesterol efflux from macrophages. By contrast, both the PPARα and PPARγ agonists were ineffective, despite their ability to produce small increases in ABCA1 expression in these cells. Table 1 Effect of GW501516 on ABCA1 expression and cholesterol efflux.
Cell line Cell ABCA1 Cholesterol
Type mRNA (% efflux (% increase) increase)
THP1 Macrophage 460 ± 150 100 ± 15
1 BR3N Fibroblast 240 ± 25 110 ± 10
FHS74 Intestinal 115 ± 30 N. D.
Percent increase was calculated from (GW-vehicle)Λtehicle x 100. Data are presented as the mean of assays performed in triplicate ± S. D. N. D., not determined.
Example 2
PPARδ is expressed in many tissues that contribute to cholesterol flux (22). To evaluate whether PPARδ plays a broad role in the regulation of reverse cholesterol transport, we evaluated GW501516 in human fibroblast and intestinal cell lines (Table 1). In 1BR3N human skin fibroblasts, the selective PPARδ agonist produced a 3.4-fold increase in ABCA1 expression and a 2-fold increase in apoA1 -specific cholesterol efflux. In FHS74 human intestinal cells (23), the selective PPARδ agonist produced a 2.1 -fold increase in ABCA1 expression. These results, combined with the effect of GW501516 in macrophages, suggest that PPARδ agonists may promote reverse cholesterol transport from multiple tissues. References
1. Lichtenstein, A. H., Kennedy, E., Barrier, P., Ernst, N. D., Grundy, S. M., Leveille, G. A., Van Home, L., Williams, C. L. & Booth, S. L. (1998) Nutr. Rev. 56, S3-S28. 5 2. Grundy, S. M. (1998) Am. J. Cardiol. 81, 18B-25B.
3. Ginsberg, H. N. (2000) J. Clin. Invest. 106, 453-458.
4. Marais, A. D. (2000) Curr. Opin. Lipidol. 11, 597-602.
5. Tall, A. R. & Wang, N. (2000) J. Clin. Invest. 106, 1205-1207.
6. von Eckardstein, A. & Assmann, G. (2000) Curr. Opin. Lipidol. 11, 627-637.
10 7. Schmitz, G., Kaminski, W. E. & Orso, E. (2000) Curr. Opin. Lipidol. 11, 493-501.
8. Brooks-Wilson, A., Marcil, M., Clee, S. M., Zhang, L.-H., Roomp, K., Van Dam, M., Yu, L., Brewer, C, Collins, J. A., Molhuizen, H. O. F., et al. (1999) Nat. Genet. 22, 336-345.
9. Bodzioch, M., Orso, E., Klucken, J., Langmann, T., Bottcher, A., Diederich, W., 15 Drobnik, W., Barlage, S., Buchler, C, Porsch-Ozcurumez, M., et al. (1999) Nat.
Genet. 22, 347-351.
10. Rust, S., Rosier, M., Funke, H., Real, J., Amoura, Z., Piette, J.-C, Deleuze, J.- F., Brewer, H. B., Duverger, N., Denefle, P., et al. (1999) Nat. Genet. 22, 352- 355.
20 11. Clee, S. M., Kastelein, J. J. P., Dam, M. v., Marcil, M., Roomp, K., Zwarts, K. Y.,
Collins, J. A., Roelants, R., Tamasawa, N., Stulc, T., et al. (2000) J. Clin. Invest.
106, 1263-1270. 12. Staels, B., Dallongeville, J., Auwerx, J., Schoonjans, K., Leitersdorf, E. &
Fruchart, J.-C. (1998) Circulation 98, 2088-2093. 25 13. Hansen, B. C. (2000) in Obesity: pathology and therapy, eds. Lockwood, D. H. &
Heffner, T. G. (Springer-Verlag, Berlin), pp. 461-489. 14. Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M.
B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., et al. (1999) N.
Engl. J. Med. 341 , 410-418. 30 15. Willson, T. M., Brown, P. J., Sternbach, D. D. & Henke, B. R. (2000) J. Med.
Chem. 43, 527-550. 16. Chinetti, G., Lestavel, S., Bocher, V., Remaley, A. T., Neve, B., Torra, I. P., Teissier, E., Minnich, A., Jaye, M., Duverger, N., et al. (2001 ) Nat. Med. 7, 53- 58.
17. Repa, J. J., Turley, S. D., Lobaccaro, J. M. A., Medina, J., Li, L., Lustig, K., 5 Shan, B., Heyman, R. A., Dietschy, J. M. & Mangelsdorf, D. J. (2000) Science
289, 1524-1529.
18. Venkateswaran, A., Laffitte, B. A., Joseph, S. B., Mak, P. A., Wilpitz, D. C, Edwards, P. A. & Tontonoz, P. (2000) Proc. Natl. Acad. Sci. USA 97, 12097- 12102.
10 19. Costet, P., Luo, Y., Wang, N. & Tall, A. R. (2000) J. Biol. Chem. 275, 28240-
28245. 20. Brown, P. J., Smith-Oliver, T. A., Charifson, P. S., Tomkinson, N. C. O., Fivush,
A. M., Sternbach, D. D., Wade, L. E., Orband-Miller, L, Parks, D. J., Blanchard,
S. G., et al. (1997) Chem. Biol. 4, 909-918. 15 21. Cobb, J. E., Blanchard, S. G., Boswell, E. G., Brown, K. K., Charifson, P. S.,
Cooper, J. P., Collins, J. L., Dezube, M., Henke, B. R., Hull-Ryde, E. A., et al.
(1998) J. Med. Chem. 41, 5055-5069. 22. Braissant, O., Foufelle, F., Scotto, C, Dauca, M. & Wahli, W. (1996)
Endocrinology 137, 354-66. 20 23. Owens, R. B., Smith, H. S., Nelson-Rees, W. A. & Springer, E. L (1976) J. Natl.
Cancer Inst. 56, 843-849.

Claims

Claims
1. A method of increasing ABCA1 activity and/or expression and promoting reverse cholesterol transport in a subject, comprising administering to the subject a therapeutically effective amount of an modulator of PPAR delta.
2. Use of a PPAR delta modulator for the manufacture of a medicament for the purpose of increasing ABCA1 activity and/or expression and promoting reverse cholesterol transport in a subject.
3. A method for testing a compound or composition for the treatment of a PPAR mediated disease or condition comprising administering a PPAR delta modulator against one or more subjects and determining the level of ABCA1 activity and/or expression.
4. A method of treatment of PPAR mediated diseases or conditions which comprises the administration of a therapeutically effective amount of a compound identified by the method of claim 3 to a patient in need thereof.
5. A method for identifying a suitable treatment regime for treating a PPAR mediated disease or condition in an individual comprising determining a regime for a compound or composition which increases ABCA1 activity and/or expression comprising administering a compound, measuring ABCA1 activity and/or expression whereby trhe determined regime provides an effective treatment.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6869975B2 (en) 2001-09-14 2005-03-22 Tularik Inc. Linked biaryl compounds
WO2007003581A1 (en) 2005-06-30 2007-01-11 Novo Nordisk A/S Phenoxy acetic acids as ppar delta activators
US7241901B2 (en) * 2002-05-04 2007-07-10 Heonjoong Kang Process for preparing thiazole derivative and the intermediate compounds for preparing the same
US7943613B2 (en) 2005-12-22 2011-05-17 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US7943612B2 (en) 2006-03-09 2011-05-17 High Point Pharmaceuticals, Llc Compounds that modulate PPAR activity, their preparation and use
US7968723B2 (en) 2004-05-05 2011-06-28 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US8053598B2 (en) 2004-05-05 2011-11-08 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US10456406B2 (en) 2013-09-09 2019-10-29 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028149A1 (en) * 1996-02-02 1997-08-07 Merck & Co., Inc. Method for raising hdl cholesterol levels
WO1998043081A1 (en) * 1997-03-26 1998-10-01 Ligand Pharmaceuticals Incorporated Treatment of gastrointestinal disease with ppar modulators
EP1023907A1 (en) * 1997-07-24 2000-08-02 Yamanouchi Pharmaceutical Co. Ltd. Medicinal compositions with cholesterol-lowering effect
WO2001000603A1 (en) * 1999-06-25 2001-01-04 Glaxo Group Limited Thiazole and oxazole derivatives and their pharmaceutical use
WO2001007066A2 (en) * 1999-07-23 2001-02-01 The University Of Dundee Ppar delta inhibitors for the treatment of cardiovascular diseases
WO2001066098A2 (en) * 2000-03-09 2001-09-13 Aventis Pharma Deutschland Gmbh Therapeutic uses of ppar mediators
WO2002007765A2 (en) * 2000-07-20 2002-01-31 Bristol-Myers Squibb Company REGULATORS OF PPARδ(β) AND THEIR USE IN THE TREATMENT OF OBESITY AND INSULIN RESISTANCE
WO2002028434A2 (en) * 2000-10-05 2002-04-11 Glaxo Group Limited Use of a ppar delta activator for treating inflammatory conditions

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020060227A (en) * 1999-11-10 2002-07-16 다케다 야쿠힌 고교 가부시키가이샤 Body weight gain inhibitors
JP2001354671A (en) * 2000-04-14 2001-12-25 Nippon Chemiphar Co Ltd ACTIVATOR FOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR delta
EP1310494B1 (en) * 2000-08-11 2012-01-25 Nippon Chemiphar Co., Ltd. PPAR (delta) ACTIVATORS
WO2002046154A1 (en) * 2000-12-05 2002-06-13 Nippon Chemiphar Co., Ltd. Peroxisome proliferator activated receptor d activators

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028149A1 (en) * 1996-02-02 1997-08-07 Merck & Co., Inc. Method for raising hdl cholesterol levels
WO1998043081A1 (en) * 1997-03-26 1998-10-01 Ligand Pharmaceuticals Incorporated Treatment of gastrointestinal disease with ppar modulators
EP1023907A1 (en) * 1997-07-24 2000-08-02 Yamanouchi Pharmaceutical Co. Ltd. Medicinal compositions with cholesterol-lowering effect
WO2001000603A1 (en) * 1999-06-25 2001-01-04 Glaxo Group Limited Thiazole and oxazole derivatives and their pharmaceutical use
WO2001007066A2 (en) * 1999-07-23 2001-02-01 The University Of Dundee Ppar delta inhibitors for the treatment of cardiovascular diseases
WO2001066098A2 (en) * 2000-03-09 2001-09-13 Aventis Pharma Deutschland Gmbh Therapeutic uses of ppar mediators
WO2002007765A2 (en) * 2000-07-20 2002-01-31 Bristol-Myers Squibb Company REGULATORS OF PPARδ(β) AND THEIR USE IN THE TREATMENT OF OBESITY AND INSULIN RESISTANCE
WO2002028434A2 (en) * 2000-10-05 2002-04-11 Glaxo Group Limited Use of a ppar delta activator for treating inflammatory conditions

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
A. BROOKS-WILSON ET AL: "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency" NATURE GENETICS, vol. 22, August 1999 (1999-08), pages 336-345, XP002215795 cited in the application *
BODZIOCH MAREK ET AL: "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease" NATURE GENETICS, NATURE AMERICA, NEW YORK, US, vol. 22, no. 4, August 1999 (1999-08), pages 347-351, XP000889766 ISSN: 1061-4036 cited in the application *
DATABASE WPI Section Ch, Week 200141 Derwent Publications Ltd., London, GB; Class B05, AN 2001-389756 XP002215800 -& WO 01 34200 A (TAKEDA CHEM IND LTD), 17 May 2001 (2001-05-17) *
DATABASE WPI Section Ch, Week 200203 Derwent Publications Ltd., London, GB; Class B02, AN 2002-026000 XP002215799 -& WO 01 79197 A (NIPPON CHEMIPHAR CO), 25 October 2001 (2001-10-25) *
DATABASE WPI Section Ch, Week 200237 Derwent Publications Ltd., London, GB; Class B03, AN 2002-339438 XP002215797 -& WO 02 14291 A, 21 February 2002 (2002-02-21) *
DATABASE WPI Section Ch, Week 200255 Derwent Publications Ltd., London, GB; Class B02, AN 2002-519654 XP002215798 -& WO 02 46154 A (NIPPON CHEMIPHAR CO), 13 June 2002 (2002-06-13) *
M. D. LEIBOWITZ ET AL.: "Activation of PPARdelta alters lipid metabolism in db/db mice" FEBS LETTERS, vol. 473, 2000, pages 333-336, XP004337162 *
S. M. CLEE ET AL: "Age and residual cholesterol efflux affect HDl cholesterol levels and coronary artery disease in ABCA1 heterozygotes" THE JOURNAL OF CLINICAL INVESTIGATION, vol. 106, no. 10, October 2000 (2000-10), pages 1263-1270, XP002215796 cited in the application *
S. RUST ET AL: "Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1" NATURE GENETICS , vol. 22, August 1999 (1999-08), pages 352-355, XP002215794 cited in the application *
SCHMITZ G ET AL: "ABC TRANSPORTERS IN CELLULAR LIPID TRAFFICKING" CURRENT OPINION IN LIPIDOLOGY, LONDON, GB, vol. 11, October 2000 (2000-10), pages 493-501, XP000992248 ISSN: 0957-9672 cited in the application *
WILLSON T M ET AL: "The PPARs: From orphan receptors to drug discovery" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 43, no. 4, 24 February 2000 (2000-02-24), pages 527-550, XP002158740 ISSN: 0022-2623 cited in the application *

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