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WO1997028149A1 - Procede pour augmenter les niveaux de cholesterol hdl - Google Patents

Procede pour augmenter les niveaux de cholesterol hdl Download PDF

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Publication number
WO1997028149A1
WO1997028149A1 PCT/US1997/001808 US9701808W WO9728149A1 WO 1997028149 A1 WO1997028149 A1 WO 1997028149A1 US 9701808 W US9701808 W US 9701808W WO 9728149 A1 WO9728149 A1 WO 9728149A1
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WIPO (PCT)
Prior art keywords
inhibitor
mammal
compound
pparδ agonist
raising
Prior art date
Application number
PCT/US1997/001808
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English (en)
Inventor
Mark D. Leibowitz
Joel P. Berger
David E. Moller
Johan Auwerx
Gregory D. Berger
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9604232.0A external-priority patent/GB9604232D0/en
Priority claimed from GBGB9604233.8A external-priority patent/GB9604233D0/en
Priority claimed from GBGB9604231.2A external-priority patent/GB9604231D0/en
Priority claimed from GBGB9604234.6A external-priority patent/GB9604234D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU18569/97A priority Critical patent/AU1856997A/en
Publication of WO1997028149A1 publication Critical patent/WO1997028149A1/fr

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    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Definitions

  • the instant invention is directed to ligands that bind to and act as agonists of the delta human peroxisome proliferator activated receptor (PPAR ⁇ ).
  • PPAR ⁇ delta human peroxisome proliferator activated receptor
  • the agonists are useful for raising high density lipoprotein levels and for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events.
  • Hyperlipidemia is a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins.
  • lipoproteins There are five classifications of lipoproteins based on their degree of density: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), intermediate density lipoproteins (IDL), and high density lipoproteins (HDL). These classifications are commonly known in the art and are described, for example, in the Merck Manual, 16th Ed. 1992 (see for example pp. 1039-1040) and "Structure and Metabolism of Plasma Lipoproteins" in Metabolic Basis of Inherited Disease, 6th Ed. 1989, pp. 1 129-1 138.
  • hyperlipidemia characterized by the existence of elevated LDL cholesterol levels.
  • the initial treatment for hypercholesterolemia is often to modify the diet to one low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy when LDL-lowering goals are not met by diet and exercise alone.
  • LDL is commonly known as the "bad” cholesterol
  • HDL is the "good” cholesterol.
  • it is desirable to lower elevated levels of LDL cholesterol it is also desirable to increase levels of HDL cholesterol.
  • HDL coronary heart disease
  • CVD coronary heart disease
  • Peroxisome proliferators are a structurally diverse group of compounds that when administered to rodents elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes of the beta-oxidation cycle. Compounds of this group include but are not limited to the fibrate class of hyperlipidemic drugs, herbicides and phthalate plasticizers. Peroxisome proliferation is also triggered by dietary or physiological factors such as a high-fat diet and cold acclimatization.
  • PPAR peroxisome proliferator activated receptor alpha
  • PPAR ⁇ peroxisome proliferator activated receptor gamma
  • PPAR ⁇ peroxisome proliferator activated receptor delta
  • Fibric acid derivatives such as clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil, produce a substantial reduction in plasma triglycerides along with moderate reduction in LDL cholesterol, and they are used particularly for the treatment of hypertriglyceridemia.
  • the PPAR ⁇ receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver.
  • the DNA sequences for the isotypes are described in Elbrecht, et al., BBRC 224 ;431-437 (1996).
  • PPAR ⁇ 2 is expressed specifically in fat cells. Tontonoz et al., Cell 79: 1147-1 156 (1994) provide evidence to show that one physiological role of PPAR ⁇ 2 is to induce adipocyte differentiation.
  • PPAR ⁇ 2 regulates the expression of genes through interaction with other proteins and binding to hormone response elements for example in the 5' flanking regions of responsive genes.
  • An example of a PPAR ⁇ 2 responsive gene is the tissue-specific adipocyte P2 gene.
  • peroxisome proliferators including the fibrates and fatty acids, activate the transcriptional activity of PPAR's, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR ⁇ subtype, which also binds thiazolidinedione antidiabetic agents with high affinity.
  • hPPAR ⁇ human nuclear receptor gene PPAR ⁇
  • PPAR ⁇ is also referred to in the literature as PPAR ⁇ and as NUC1 , and each of these names refers to the same receptor; in Schmidt et al, the receptor is referred to as NUCl .
  • hNUClB a human PPAR subtype, hNUClB.
  • the amino acid sequence of hNUC IB differs from human PPAR ⁇ (referred to therein as hNUCl) by one amino acid, i.e., alanine at position 292.
  • hNUCl human PPAR ⁇
  • alanine alanine at position 292.
  • the authors suggest that hNUC IB protein represses hPPAR ⁇ and thyroid hormone receptor protein activity.
  • no function had been identified for the PPAR ⁇ subtype.
  • ligands which are agonists of PPAR ⁇ are useful for raising HDL levels. Since there is a continued need for methods to increase HDL levels in mammals, particularly humans, the present invention addresses this need by providing novel methods and compounds useful for raising HDL.
  • One object of this invention is to provide a method for raising high density lipoprotein (HDL) plasma levels in a mammal in need of such treatment comprising administering an HDL-raising amount of a PPAR ⁇ agonist.
  • HDL high density lipoprotein
  • a second object is to provide methods for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events in a mammal in need of such treatment comprising administering an HDL-raising amount of a PPAR ⁇ agonist.
  • a third object is to provide methods for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events in a mammal in need of such treatment comprising administering an HDL-raising amount of a PPAR ⁇ agonist in combination with one or more additional active agents, for example an hydroxymethylglutaryl coenzyme A (HMG- CoA) reductase inhibitor.
  • HMG- CoA hydroxymethylglutaryl coenzyme A
  • a fourth object is to describe and provide compounds which are PPAR ⁇ agonists and which are useful for the above-described methods. Additional objects will be evident from the following description.
  • PPAR ⁇ agonists which are intended to be within the scope of this invention are those which have (1 ) an IC50 equal to or less than 10 ⁇ M in the hPPAR ⁇ binding assay, and (2) an EC50 equal to or less than 10 ⁇ M in the hPPAR ⁇ transactivation assay.
  • the PPAR ⁇ agonists have an IC50 equal to or less than 100 nM in the hPPAR ⁇ binding assay, and an EC50 equal to or less than 100 nM in the hPPAR ⁇ transactivation assay. More preferably, the PPAR ⁇ agonists have an IC50 equal to or less than 50 nM in the hPPAR ⁇ binding assay, and an EC50 equal to or less than 50 nM in the hPPAR ⁇ transactivation assay. Most preferably, the PPAR ⁇ agonists have an IC50 equal to or less than 10 nM in the hPPAR ⁇ binding assay, and an EC50 equal to or less than 10 nM in the hPPAR ⁇ transactivation assay. Compounds which are PPAR ⁇ agonists as defined above may also have activity at the PPAR ⁇ or PPAR ⁇ receptors.
  • the hPPAR ⁇ binding assay comprises the steps of:
  • step (c) subjecting each of the test samples and the control sample from step (b) to centrifugation at 4 °C until the charcoal is pelleted; then
  • step (d) counting a portion of the supernatant fraction of each of the test samples and the control sample from step (c) in a liquid scintillation counter and analyzing the results to determine the IC50 of the test compound.
  • a liquid scintillation counter preferably at least four test samples of varying concentrations of a single test compound are prepared in order to determine the IC50.
  • the hPPAR ⁇ transactivation assay comprises the steps of:
  • step (b) incubating the cells from step (a) for 16 to 48 hours, preferably about 20 hours, at 37°C in an atmosphere of 10% CO2 in air;
  • step (c) washing the cells from step (b) with alpha MEM;
  • step (d) preparing multiple test cell groups by incubating separate groups of the cells from step (c) with the test compound in alpha MEM containing 5% charcoal stripped FCS, 10 mM HEPES, and 500 mg/ml G418, for 24 to 48 hours, preferably about 24 hours, at 37°C in an atmosphere of 10% C ⁇ 2 in air, wherein the concentration of the test compound in each test cell group is different, and preparing a control cell group by incubating a further separate group of the cells from step (c) under the same conditions but without the test compound; then
  • step (e) preparing cell lysates from each of the test cell groups and the control cell group of step (d) using an aqueous detergent lysis buffer
  • step (f) measuring the luciferase activity of the test cell groups and the control cell group of step (e) and analyzing the results to determine the EC50 of the test compound.
  • test cell groups of varying concentrations of a single test compound are prepared in order to determine the EC50.
  • Examples of compounds which are PPAR ⁇ agonists include, but are not limited to, the following compounds A through F and the pharmaceutically acceptable salts and esters thereof:
  • Additional compounds which are PPAR ⁇ agonists and are included within the scope of this invention include but are not limited to those found in the following U.S provisional applications: application no. 60/01 1093 filed February 2, 1996 (Merck attorney docket no.
  • the instant invention provides methods for preventing or reducing the risk of developing atherosclerosis, comprising the administration of a prophylactically effective amount, or more particularly an HDL-raising amount, of a PPAR ⁇ agonist, alone or in combination with one or more additional pharmaceutically active agents, to a mammal, particularly human, who is at risk of developing atherosclerosis.
  • PPAR ⁇ agonists can also be used in methods for treating, halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising the administration of a therapeutically effective amount, or more particularly an HDL-raising amount, of a PPAR ⁇ agonist, alone or in combination with one or more additional pharmaceutically active agents, to a mammal, particularly human, who already has atherosclerotic disease.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • the instant invention further provides methods for preventing or reducing the risk of a first or subsequent (where the potential exists for recurrence) atherosclerotic disease event, comprising the administration of a prophylactically effective amount, or more particularly an HDL-raising amount, of a PPAR ⁇ agonist, alone or in combination with one or more additional pharmaceutically active agents, to a mammal, particularly human, who is at risk for having an atherosclerotic disease event.
  • corthelial disease event is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication.
  • Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures.
  • Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks.
  • Intermittent claudication is a clinical manifestation of peripheral vessel disease. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease event are those for whom the potential for recurrence of such an event exists.
  • Persons to be treated with the instant therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event.
  • Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein cholesterol, high levels of low density lipoprotein cholesterol, and a family history of atherosclerotic cardiovascular disease.
  • People who are identified as having one or more of the above-noted risk factors are intended to be included in the group of people considered at risk for developing atherosclerotic disease. People identified as having one or more of the above-noted risk factors, as well as people who already have atherosclerosis, are intended to be included within the group of people considered to be at risk for having an atherosclerotic disease event.
  • composition is intended to encompass a product comprising the specified ingredients, in specified amounts where amounts are specified, as well as any product which results directly or indirectly from combination of the specified ingredients, in the specified amounts where amounts are specified.
  • active PPAR ⁇ agonist compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be inco ⁇ orated directly with the food of the diet.
  • these active compounds may be inco ⁇ orated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray. Oral administration is preferred.
  • Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • Therapeutically effective amounts, prophylactically effective amounts and/or high density lipoprotein-raising amounts of the PPAR ⁇ agonist are suitable for use in the compositions and methods of the present invention.
  • the term "therapeutically effective amount” is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a clinician, such as a researcher, veterinarian, medical doctor or osteopathic doctor.
  • prophylactically effective amount is intended to mean that amount of a drug or pharmaceutical agent that will prevent or reduce the risk of occurrence of a medical condition, such as atherosclerosis or an atherosclerotic disease event.
  • high density lipoprotein-raising amount is intended to mean an amount of a drug or pharmaceutical agent that will elevate a subject's plasma HDL level above the level it was at prior to administration of the drug or pharmaceutical agent. Measurement of plasma HDL levels can be performed using any medically acceptable procedures known to those skilled in the medical arts, including assay kits designed for use directly by consumers.
  • the dosage regimen utilizing a PPAR ⁇ agonist is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or derivative thereof employed. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the pu ⁇ ose of determining an appropriate HDL-raising amount of the PPAR ⁇ agonist, as well as the therapeutically effective amounts of the PPAR ⁇ agonist needed to prevent, counter, or arrest the progress of the condition.
  • the compounds of the present invention can be administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, once a day or given in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligram to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams.
  • the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the PPAR ⁇ agonist may be administered alone or in combination with one or more additional active agents.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a PPAR ⁇ agonist and one or more additional active agents, as well as administration of the PPAR ⁇ agonist and each active agent in its own separate pharmaceutical dosage formulation.
  • a PPAR ⁇ agonist and an HMG-CoA reductase inhibitor can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations.
  • the PPAR ⁇ agonist and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially; combination therapy is understood to include all these regimens.
  • the PPAR ⁇ agonist may be administered in combination with one or more of the following active agents: an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent such as a cholesterol biosynthesis inhibitor, for example an HMG-CoA reductase inhibitor, an HMG- CoA synthase inhibitor, a squalene epoxidase inhibitor, or a squalene synthetase inhibitor (also known as squalene synthase inhibitor); an acyl-coenzyme A: cholesterol acyltransferase (AC AT) inhibitor such as melinamide; probucol; nicotinic acid and the salts thereof and niacinamide; a cholesterol abso ⁇ tion inhibitor such as beta- sitosterol; a bile acid sequestrant anion exchange resin such as cholestyramine, colestipol or a dialkylaminoalkyi derivatives of a cross-linked dex
  • the PPAR ⁇ agonist can be administered in combination with more than one additional active agent, for example, a combination of PPAR ⁇ agonist with an HMG-CoA reductase inhibitor and aspirin, or PPAR ⁇ agonist with an HMG-CoA reductase inhibitor and a beta blocker.
  • the PPAR ⁇ agonist is preferably administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor.
  • HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester, free acid and lactone forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, free acids and lactone forms is included within the scope of this invention.
  • Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231 ,938 at col. 6, and WO 84/02131 at pp. 30-33.
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin (MEVACOR®; see US Patent No. 4,231 ,938), simvastatin (ZOCOR®; see US Patent No. 4,444,784), pravastatin sodium (PRAVACHOL®; see US Patent No. 4,346,227), fluvastatin sodium (LESCOL®; see US Patent No. 5,354,772), atorvastatin calcium (LIPITOR®; see US Patent No. 5,273,995) and rivastatin (also known as cerivastatin; see US Patent No. 5,177,080).
  • lovastatin MVACOR®
  • simvastatin ZOCOR®
  • pravastatin sodium PRAVACHOL®
  • fluvastatin sodium see US Patent No. 5,354,772
  • atorvastatin calcium LIPITOR®
  • rivastatin also known as cerivastatin; see US Patent No. 5,177,080.
  • HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996).
  • the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.
  • HMG-CoA reductase inhibitors Dosage information for HMG-CoA reductase inhibitors is well known in the art, since several HMG-CoA reductase inhibitors are marketed in the U.S.
  • the daily dosage amounts of the HMG-CoA reductase inhibitor may be the same or similar to those amounts which are employed for anti- hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR).
  • PDR Physicians' Desk Reference
  • the oral dosage amount of HMG-CoA reductase inhibitor is from about 1 to 200 mg/day, and more preferably from about 5 to 160 mg/day.
  • dosage amounts will vary depending on the potency of the specific HMG-CoA reductase inhibitor used as well as other factors as noted above.
  • An HMG-CoA RI which has sufficiently greater potency may be given in sub-milligram daily dosages.
  • the daily dosage amount for simvastatin may be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg.
  • the daily dosage amount for atorvastatin calcium may be in the range of from 1 mg to 160 mg, and more particularly from 5 mg to 80 mg.
  • Oral administration may be in single or divided doses of two, three, or four times daily, although a single daily dose of the HMG-CoA reductase inhibitor is preferred.
  • an HDL-raising amount of a PPAR ⁇ agonist can be used for the preparation of a medicament useful for raising the plasma level of high density lipoprotein in mammals, particularly in humans.
  • a prophylactically effective amount of a PPAR ⁇ agonist can be used for the preparation of a medicament useful for preventing or reducing the risk of developing atherosclerosis, and for preventing or reducing the risk of having a first or subsequent atherosclerotic disease event in mammals, particularly in humans.
  • a therapeutically effective amount of a PPAR ⁇ agonist can be used for the preparation of a medicament useful for treating atherosclerosis in mammals, particularly in humans.
  • the PPAR ⁇ agonist can be admixed together wit a therapeutically effective amount of one or more additional active agents selected from the group consisting of: an LDL-lowering agent; an antihyperhpidemic agent; an HDL-raising agent; an HMG-CoA synthase inhibitor; a squalene epoxidase inhibitor; a squalene synthetase inhibitor ; an acyl-coenzyme A: cholesterol acyltransferase inhibitor; probucol; nicotinic acid and the salts thereof; niacinamide; a cholesterol abso ⁇ tion inhibitor; a bile acid sequestrant anion exchange resin; a low density lipoprotein receptor inducer; clofibrate, fenofibrate, and gemfibrizol; vitamin B6 and the pharmaceutically acceptable salts thereof; vitamin B12; an anti-oxidant vitamin; a beta-blocker; an an an LDL-lowering agent; an antihyperhpid
  • the PPAR ⁇ agonist and a therapeutically effective amount of an HMG-CoA reductase inhibitor can be admixed together for the preparation of a medicament useful for the above- described treatments.
  • the PPAR ⁇ agonist and a therapeutically effective amount of an HMG-CoA reductase inhibitor selected from the pharmaceutically acceptable lactone, free acid, ester and salt forms of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin can be admixed together for the preparation of a medicament suitable for oral administration which is useful for the above-described treatments.
  • the HMG-CoA reductase inhibitor used for the medicament preparation is lovastatin or simvastatin.
  • Compounds which are PPAR ⁇ agonists within the scope of this invention can be identified by the following procedures. To evaluate IC50 or EC50 values the compounds were titrated in the appropriate assay using different concentrations of the compound to be tested. To obtain the appropriate values (%Inhibition-IC50, or %Activation-EC50), the data resulting from the assays were then analyzed by determining the best fit of a 4 parameter function to the data using the Levenberg-Marquardt non-linear fitting algorithm in Kaleidagraph (Synergy Software, Reading, PA).
  • hPPAR ⁇ human nuclear receptor gene PPAR ⁇
  • gst glutathione-S-transferase
  • EDTA ethylenediamine- tetraacetic acid
  • HEPES N-[2-hydroxyethyl]-piperazine-N'-[2- ethanesulfonic acid ⁇
  • FCS fetal calf serum
  • Lipofectamine is a 3:1
  • G418 is geneticin;
  • MEM is Minimum Essential Medium;
  • Opti MEM 1 Reduced-Serum Medium is an aqueous composition containing HEPES buffer, 2400 mg/L sodium bicarbonate, hypoxanthine, thymidine, sodium pyruvate, L-glutamine, trace elements, growth factors, and phenol red reduced to 1.1 mg/L;
  • Luciferase Assay Reagent (in re-constituted form) is an aqueous composition containing 20 mM tricine, 1.07 mM (MgC ⁇ 3)4Mg(OH)2*5H2 ⁇ , 2.67 m
  • AD-5075 has the following structure:
  • Compound D can also be used in place of AD-5075 in the hPPAR ⁇ 2 binding assay.
  • Alpha MEM is an aqueous composition having the following components:
  • Human PPAR ⁇ was prepared as a gst-fusion protein in E. coli.
  • the full length human cDNA for PPAR ⁇ was subcloned into the PGEX-KT expression vector (Pharmacia).
  • E. coli containing the plasmid were grown, induced, and then harvested by centrifugation. The resuspended pellet was broken in a French press and debris was removed by centrifugation at 12,000Xg.
  • Receptor was purified from the supernatant by affinity chromatography on glutathione sepharose. After application to the column, and 1 wash the receptor was eluted with glutathione. Glycerol was added to stabilize the receptor and aliquots were frozen at -80 °C for later use.
  • HlCompound D Displacement Assay For each assay, an aliquot of receptor from Example 1 A (1 : 1000-1 :3000 dilution) was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ l/100 ml ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreotol, 5 ⁇ g/ml aprotinin, 2 ⁇ g/ml leupeptin, 2 ⁇ g/ml benzamide and 0.5 mM phenylmethylsulfonylfluoride) containing 5-10% COS-1 cell cytoplasmic lysate and 2.5 nM labeled ([3H2]Compound D, 17 Ci/mmole), with or without test compound (incubation without test compound serves as the control for comparison pu ⁇ oses).
  • TEGM 10 mM Tris, pH 7.2, 1 m
  • Assays were incubated for about 16 hours at 4 °C in a final volume of 300 ⁇ l. Unbound ligand was removed by addition of 200 ⁇ l dextran/gelatin- coated charcoal, on ice, for about 10 minutes. After centrifugation at 3000 ⁇ m for 10 min at 4 °C, 200 ⁇ l of the supernatant fraction was counted in a liquid scintillation counter. In this assay the KD for Compound D is about 1 nM.
  • Human PPAR ⁇ 2 was prepared as a gst-fusion protein in E. coli.
  • the full length human cDNA for PPAR ⁇ 2 was subcloned into the PGEX-2T expression vector (Pharmacia).
  • E. coli containing the plasmid were propagated, induced, and then harvested by centrifugation. The resuspended pellet was broken in a French press and debris was removed by centrifugation at 12,000Xg.
  • Recombinant human PPAR ⁇ 2 receptor was purified from the supernatant by affinity chromatography on glutathione sepharose. After application to the column, and 1 wash, receptor was eluted with glutathione. Glycerol was added to stabilize the receptor and aliquots were frozen at -80 °C for later use.
  • Assays were incubated for about 16 hours at 4 °C in a final volume of 300 ⁇ l. Unbound ligand was removed by addition of 200 ⁇ l dextran/gelatin- coated charcoal, on ice, for about 10 minutes. After centrifugation at 3000 ⁇ m for 10 min at 4 °C, 200 ⁇ l of the supernatant fraction was counted in a liquid scintillation counter. In this assay the KD for AD- 5075 is about 1 nM.
  • Plasmids The chimeric receptor expression construct, pSG5- hPPAR ⁇ /GR, was prepared by inserting the DNA binding domain of the murine glucocorticoid receptor adjacent to the ligand binding domain of hPPAR ⁇ .
  • the glucocorticoid receptor-responsive reporter vector, pMMTV/luc/neo contains the murine mammary tumour virus (MMTV) promoter adjacent to the luciferase gene (luc) and the neomycin resistance gene (neo). It was constructed from pMMTV/luc.
  • MMTV murine mammary tumour virus
  • luc luciferase gene
  • neomycin resistance gene neomycin resistance gene
  • pMMTV/luc/neo DNA was cut with Pvu I.
  • the PPAR- responsive reporter construct, pPPRE-luc contained 3 copies of a generic PPRE placed adjacent to the thymidine kinase minimal promoter and the luciferase reporter gene.
  • the transfection control vector, pCMV-lacZ contains the galactosidase Z gene under the regulation of the cytomegalovirus promoter.
  • CHO-K1 cells were seeded overnight at 6x10 cells /60 mm dish in alpha MEM additionally containing 10% FCS, 10 mM HEPES,
  • cells After being incubated for 3 days, cells were subcultured by diluting the cell suspension 1/1250 and 1/6250 and placing the cells in a 100 mm culture dish. Selection of the stable cell lines was initiated the next day by adding 500 ⁇ g/ml G418 to the medium. Cells were routinely fed with the selection media for 1 month at which time 120 colonies were picked and transferred to 24 well culture plates. Ten days later, confluent colonies were transferred to a 6 well plate to maintain stocks and to 96 well plates to assay for luciferase activity. Positive clones were characterized and validated by titrating 4 known agonists on each clone. Two clones, g2B2P2D9 and d2A5P2G3, were selected for screening pu ⁇ oses.
  • hPPAR ⁇ /GR transactivation screens in stably transfected CHO-K1 cells The hPPAR ⁇ /GR stable CHO-K1 cell lines from Example 3A were seeded at 1x10 cells/well into 96 well cell culture plates in alpha MEM containing 10% FCS, 10 mM HEPES, and 500 mg/ml G418 at 37°C in an atmosphere of 10% C ⁇ 2 in air. After a 20 hour incubation, cells were washed once with alpha MEM and then incubated at 37°C in an atmosphere of 10% C ⁇ 2 in air in alpha MEM containing 5% charcoal stripped FCS, 10 mM HEPES, and 500 mg/ml G41 .
  • the cells were incubated for 24 hours in the absence of test compound or in the presence of a range of concentrations of test compound.
  • Cell lysates were prepared from washed cells using Reporter Lysis Buffer (Promega) according to the manufacturer's directions. Luciferase activity in cell extracts was determined using Luciferase Assay Reagent buffer (Promega) in a ML3000 luminometer (Dynatech Laboratories).
  • Plasmids The chimeric receptor expression construct, pSG5- hPPAR ⁇ 2/GR was prepared, and the production of stable cell lines was performed, according to the procedures described in Example 3A, except that hPPAR ⁇ 2 was substituted for the hPPAR ⁇ used therein.
  • hPPAR ⁇ 2/GR transactivation screens in stably transfected CHO-K 1 cells The assay is performed as described in Example 3B, except that hPPAR ⁇ 2/GR stable CHO-K 1 cell lines are employed in place of the hPPAR ⁇ /GR stable CHO-K 1 cell lines.
  • Table 1 shows the results of the hPPAR ⁇ and hPPAR ⁇ 2 binding assay and transactivation assay for the listed compounds.
  • the wild type receptor construct, pSG5-hPPAR ⁇ 2 was prepared by inserting the full-length hPPAR ⁇ 2 cDNA adjacent to the SV40 promoter in pSG5.
  • the wild type receptor construct, pJ3- hPPAR ⁇ was prepared by placing the hPPAR ⁇ cDNA adjacent to the SV40 promoter in pJ3 omega.
  • COS-1 cells were seeded at 0.5 X IO 5 cells/dish into 24 well plates in Dulbecco's modified Eagle medium (high glucose) containing 10% charcoal stripped fetal calf serum, nonessential amino acids, 100 units/ml Penicillin G and 100 ⁇ g/ml Streptomycin sulfate at 37°C in a humidified atmosphere of 10% CO2. After 24 hours, transfections were performed with Lipofectamine (Gibco-BRL, Gaithersburg, MD) according to the instructions of the manufacturer.
  • transfection mixes contained 0.15 mg of hPPAR ⁇ 2 or hPPAR ⁇ expression vector, 0.15 mg of reporter vector pPPRE-luc and 0.001 mg of pCMV-lacZ as an internal control of transfection efficiency.
  • Compounds demonstrating significant agonist activity in the above primary screen were further characterized by incubation with transfected cells for 48 hours across a range of concentrations. Luciferase activity was determined as described above.
  • hPPAR ⁇ l cDNA can be used in place of hPPAR ⁇ 2 cDNA in the methods described in Example 5 to make the wild type receptor construct, pSG5-hPPAR ⁇ l.
  • db/db Mice are obese, highly insulin resistant animals. The db locus has been shown to code for the leptin receptor. These animals are substantially hypertriglyceridemic and hyperglycemic.
  • mice Male db/db mice (10-11 week old C57B1/KFJ, Jackson Labs, Bar Harbor, ME) were housed 5/cage and allowed ad lib. access to ground Purina rodent chow and water. The animals, and their food, were weighed every 2 days and were dosed daily by gavage with vehicle (0.5% carboxymethylcellulose) alone or with vehicle containing test compound at the indicated dose. Drug suspensions were prepared daily. Plasma glucose, triglyceride, and cholesterol concentrations were determined from blood obtained by tail bleeds at 3-5 day intervals during the study period.
  • Glucose, triglyceride, and cholesterol determinations were performed on a Boehringer Mannheim Hitachi 91 1 automatic analyzer (Boehringer Mannheim, Indianapolis, IN) using heparinized plasma diluted 1 :5, or 1 :6 (v/v) with normal saline. Lean animals were age-matched heterozygous mice maintained in the same manner.
  • Lipoprotein analysis was performed on either serum, or EDTA treated plasma obtained by heart puncture from anesthetized animals at the end of the study. Apolipoprotein concentrations were determined by ELISA, and cholesterol particles were analyzed by FPLC, precipitation, or ultracentrifugation. Total liver RNA was prepared from tissue that had been frozen on liquid nitrogen at the time of euthanasia. Apolipoprotein mRNA was analyzed on Northern Blots using specific probes for rat proteins.
  • HDL was separated from apo B-containing lipoproteins by dextran sulfate precipitation.
  • Cholesterol was measured enzymatically using a commercially available cholesterol kit (Boehringer Mannheim Biochemicals, Indianapolis, IN) and spectrophotometrically quantitated on a microplate reader (EL 311; Bio-Teck Instruments, Winooski, VT).
  • Table 2 shows the ratio of HDL cholesterol to the sum of VLDL + LDL cholesterol for db/db mice treated for 12 days (once daily dosing by oral gavage) with the indicated compound. Values shown represent the mean of 2 pools of semm each made from 4-5 individual animals. Determinations performed both on lipoprotein particles separated by ultracentrifugation and by precipitation of non- HDL cholesterol from whole serum. BRL 49653 is a known PPAR ⁇ selective agent (see J. Med. Chem. 1994, 37:3977-3985).
  • Table 3 shows the semm values following 14 days of dosing in the same experiment as described above for table 2.
  • Step 2 Preparation of 4-(3-(2-propyl-3-hydroxy-4-acetyl- phenoxy propyloxy phenoxy acetic acid
  • Step 1 Preparation of:
  • Step A Preparation of l -bromo-3-(2-propyl-3- hvdroxy-4-propionyl-phenoxy)propane
  • Step B Preparation of methyl 3-chloro-4-(3-(2- propyl-3-hydroxy-4-propionylphenoxy)propylthio)- phenylacetate
  • the organic was dried over magnesium sulfate, filtered and concentrated to an oil.
  • the oil was applied to a silica gel column packed with hexane/methylene chloride (2: 1). The column was eluted with this mobile phase until the product began to appear in the eluant. The mobile phase was switched to 100% methylene chloride and elution continued until all the product was recovered.
  • Step 3 Preparation of 3-Chloro-4-(3-(2-propyl-3-hydroxy-4-(l- hydroxyliminopropyl)phenoxy)-propylthio)phenylacetic acid (Compound B)
  • Step 1 Preparation of l -bromo-3-(2-hydroxy-3-propyl-4- propionylphenoxy)propane
  • Step 2 Preparation of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy- 4-propionylphenoxy)propylthio)phenylacetate
  • the organic was washed once more with pH 4 buffer, then water.
  • the organic was dried over magnesium sulfate, filtered and concentrated to an oil.
  • the oil was applied to a silica gel column packed with hexane/methylene chloride (2:1 ). The column was eluted with this mobile phase until the product began to appear in the eluant. The mobile phase was switched to 100% methylene chloride and elution continued until all the title compound was recovered.
  • Step 3 Preparation of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy- 4-( 1 -hydroxyiminopropyl)phenoxy )propylthio)- phenylacetate
  • Step 5 Preparation of methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6- benz-[4.51-isoxazoloxy)propylthio)phenylacetate
  • Step 6 Preparation of 3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-l4,5]- isoxazoloxy)propylthio)-phenylacetic acid (Compound C)
  • Step 1 Preparation of 2,4-dihydroxy-3-propyl- trifluoroacetophenone
  • Step 3 Preparation of methyl 3-chloro-4-(3-(2-propyl-3- trifIuoromethyl-6-benz- [4,5]-isoxazoloxy)propylthio) phenylacetic acid
  • Step 4 Preparation of 3-chloro-4-(3-(2-propyl-3-trifluoromethyl- 6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetic acid (Compound D)
  • reaction mixture continued to be stirred for 20 minutes, then was poured into a beaker containing ice.
  • the reaction flask was then rinsed with water and ether, and the washings were added to the beaker.
  • the organic layer was separated, washed with water, dried over MgS04, and concentrated.
  • Column chromatography silica gel 60, 50% methylene chloride in hexane gave the title compound.
  • Step 5 Preparation of 3-chloro-4-(3-t3-phenyl-7- propylbenzofuran-6-yloxy)propylthio)phenylacetic acid (Compound E)
  • Step 3 Preparation of methyl 3-propyl-4-hvdroxyphenylacetate A solution of methyl 3-allyl-4-hydroxyphenylacetate (1.71 grams) and palladium (10 wt.% on activated carbon) (0.27 grams) in ethyl acetate (30 mL) was hydrogenated at 50 PSI for 2 hours. The reaction mixture was filtered and concentrated to afford the title compound.
  • Step 4 Preparation of methyl 3-propyl-4-(3-(3-trifluoromethyl-7- propyl-6-benz-[4.51-isoxazoloxy)-propylthio phenylacetate
  • Step 5 Preparation of 3-propyl-4-(3-(3-trifluoromethyl-7-propyl- 6-benz-[4,5]-isoxazoloxy)-propylthio)phenylacetic acid

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Abstract

Cette invention se rapporte à des composés qui sont des agonistes de PPARδ. Ces composés sont utiles pour augmenter les niveaux de plasma à lipoprotéines à haute densité (HDL) chez des mammifères et pour empêcher, arrêter ou ralentir la progression de maladies cardiovasculaires du type athérosclérose et des états et événements pathologiques apparentés. Ces agonistes de PPARδ peuvent être administrés seuls ou associés à des agents actifs additionnels tels que des agents abaissant le cholestérol LDL (à lipoprotéines basse densité).
PCT/US1997/001808 1996-02-02 1997-01-31 Procede pour augmenter les niveaux de cholesterol hdl WO1997028149A1 (fr)

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