EP1389044A1 - Ppar-alpha-gamma ligands or agonists for the treatment of inflammation - Google Patents

Ppar-alpha-gamma ligands or agonists for the treatment of inflammation

Info

Publication number
EP1389044A1
EP1389044A1 EP02731386A EP02731386A EP1389044A1 EP 1389044 A1 EP1389044 A1 EP 1389044A1 EP 02731386 A EP02731386 A EP 02731386A EP 02731386 A EP02731386 A EP 02731386A EP 1389044 A1 EP1389044 A1 EP 1389044A1
Authority
EP
European Patent Office
Prior art keywords
pparγ
pparα
compound
binding
simultaneously binding
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02731386A
Other languages
German (de)
French (fr)
Other versions
EP1389044A4 (en
Inventor
Samuel D. Wright
Tian-Quan Cai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and 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
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1389044A1 publication Critical patent/EP1389044A1/en
Publication of EP1389044A4 publication Critical patent/EP1389044A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • a key step in the process of inflammation is the ingress of leukocytes into inflammed tissue.
  • the affected tissue responds to the inflammatory insult by the elaboration of cytokines, chemotactic factors, and adhesion molecules. These molecules serve in the attraction of leukocytes.
  • leukocytes respond to these factors by adhesion, migration, and elaboration of further cytokines and chemotactic factors. It is thus clear that inflammation requires the response of both the target tissue and the leukocytes.
  • This dual contribution is illustrated by the failure of inflammation to occur in animals deficient in leukocyte adhesion molecules (beta-2 integrins) or in animals deficient in the tissue expression of the counterreceptor for integrins, ICAM-1.
  • This invention involves administration of an agent that binds to transcription factors both in tissues and in leukocytes.
  • PPARs Peroxisome proliferator-activated receptors
  • ⁇ , ⁇ and ⁇ Three distinct PPARs, termed ⁇ , ⁇ and ⁇ , have been described. Each one is encoded by a separate gene. PPARs are characterized by distinct tissue distribution patterns and metabolic functions.
  • PPAR ⁇ is a transcription factor expressed in adipose tissues, cells of the colon, and in tissue macrophages.
  • ligands for PPAR ⁇ suppress the expression of proinflammatory molecules (Nature 391:82, Nature 391;79: Cell 93, 241; Cell 93; 229 (1998)) and may have anti-inflammatory action in vivo (JCI 104: 383, 1999). It is noteworthy that strong anti-inflammatory activity was observed in a model of colon inflammation and PPAR ⁇ is strongly expressed in the colon.
  • PPAR ⁇ is a homologous transcription factor with a distinct expression pattern being present in liver, monocytes, smooth muscle cells and other tissues. Recent studies indicate that agonists of PPAR ⁇ blunt production of pro-inflammatory cytokines (Nature 393: 790 (1998), Circulation 99: 3125 (1999)).
  • the invention encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ or concomitantly administering a compound that selectively binds PPAR ⁇ with a compound that selectively binds PPAR ⁇ in an amount that is effective to treat or prevent the inflammatory disease or condition.
  • the invention also encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ or concomitantly administering a compound that selectively binds and activates PPAR ⁇ with a compound that selectively binds and activates PPAR ⁇ in an amount that is effective to treat or prevent the inflammatory disease or condition.
  • the present invention encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ or concomitantly administering a compound that selectively binds PPAR ⁇ with a compound that selectively binds PPAR ⁇ in an amount that is effective to treat or prevent the inflammatory disease or condition.
  • Compounds that are capable of simultaneously binding PPAR ⁇ and PPAR ⁇ or "dual ligands" are defined as those compounds with half-maximal concentration potencies (IC5 ⁇ 's or KI's) for displacement of radioligand binding to hPPAR ⁇ vs. hPPAR ⁇ that differ by less than 30-fold as measured by the human PPAR ⁇ and PPAR ⁇ binding assays described below. All other compounds binding to PPAR ⁇ and/or PPAR ⁇ that fall outside this definition are considered compounds that selectively bind either PPAR ⁇ or PPAR ⁇ for purposes of this specification.
  • An embodiment of the invention encompasses administering the compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ .
  • An embodiment of the invention encompasses the instant method wherein the compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPAR ⁇ vs. hPPAR ⁇ that differs by less than 20-fold as measured by the human PPAR ⁇ and PPAR ⁇ binding assays.
  • Another embodiment is wherein the compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPAR ⁇ vs.
  • hPPAR ⁇ that differs by less than 10-fold as measured by the human PPAR ⁇ and PPAR ⁇ binding assays.
  • the compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPAR ⁇ vs. hPPAR ⁇ that differs by less than 5-fold as measured by the human PPAR ⁇ and PPAR ⁇ binding assays.
  • IC50 or KI half-maximal concentration potency
  • the compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPAR ⁇ vs. hPPAR ⁇ differ by less than 2-fold as measured by the human PPAR ⁇ and PPAR ⁇ binding assays.
  • Another embodiment of the invention encompasses the instant method wherein the compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ is orally active.
  • compounds that are orally active means compounds that produce a therapeutic response following oral ingestion of the compound.
  • Another embodiment of the invention encompasses the instant method wherein the compound that is capable of simultaneously binding PPAR ⁇ and PPAR ⁇ possesses a long duration of action.
  • compounds that possess a long duration of action means compounds that have a half-life equal to or exceeding about 1 hour.
  • Another embodiment of the invention encompasses the instant method wherein the inflammatory disease or condition is inflammatory bowel syndrome.
  • Another embodiment of the invention encompasses the instant method wherein the inflammatory disease or condition is arthritis.
  • the inflammatory disease or condition is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, and juvenile arthritis.
  • the compounds of the present invention that can be used in the treatment or prevention of an inflammatory disease or condition are compounds that have both PPAR ⁇ and PPAR ⁇ activity, which are defined in terms of PPAR agonism or in terms of binding to the PPAR receptors, partially displacing other compounds that are excellent PPAR ligands.
  • Another embodiment of the invention encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ or concomitantly administering a compound that selectively binds and activates PPAR ⁇ with a compound that selectively binds and activates PPAR ⁇ in an amount that is effective to treat or prevent the inflammatory disease or condition.
  • Compounds that are capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ or "dual PPAR ⁇ /PPAR ⁇ agonists" are defined as those compounds that exhibit both significant PPAR ⁇ and PPAR ⁇ agonism as well as half- maximal concentration potencies (EC5 ⁇ 's) for activation of hPPAR ⁇ vs. hPPAR ⁇ that differ by less than 30-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay, which are described below.
  • Compounds that exhibit both significant PPAR ⁇ and PPAR ⁇ agonism are those compounds exhibiting >50% of the maximal effects of rosiglitazone (on human PPAR ⁇ ) and >50% of the maximal effects of fenofibrate (on human PPAR ⁇ ) on both receptors as measured by the cell-based transactivation assay or cell-free co-activator association assay. It is these compounds that also exhibit half-maximal concentration potencies (ECso's) for activation of hPPAR ⁇ vs. hPPAR ⁇ that differ by less than 30-fold that are considered "dual PPAR ⁇ /PPAR ⁇ agonists" for purposes of this specification.
  • ECso's half-maximal concentration potencies
  • a compound that exhibits >50% of the maximal effects of rosiglitazone on human PPAR ⁇ but is outside the 30 fold activation difference described above is considered a compound that selectively binds and activates PPAR ⁇ . Rosiglitazone is an example of such a compound.
  • a compound that exhibits >50% of the maximal effects of fenofibrate on human PPAR ⁇ but is outside the 30 fold activation difference described above is considered a compound that selectively binds and activates PPAR ⁇ .
  • Fenofibrate is an example of such a compound.
  • An embodiment of the invention encompasses administering the compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ .
  • the compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ has a half-maximal concentration potency (EC50) for activation of hPPAR ⁇ vs. hPPAR ⁇ that differs by less than 20-fold as measured by the cell-based transactivation assay or cell-free co-activator association assay. Also within this embodiment is encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ has a half- maximal concentration potency (EC50) for activation of hPPAR ⁇ vs.
  • EC50 half-maximal concentration potency
  • hPPAR ⁇ that differs by less than 10-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay. Also within this embodiment is encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ has a half-maximal concentration potency (EC50) for activation of hPPAR ⁇ vs. hPPAR ⁇ that differs by less than 5-fold as measured by the cell-based transactivation assay or cell-free co-activator association assay.
  • EC50 half-maximal concentration potency
  • the compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ has a half- maximal concentration potency (EC5 ⁇ 's) for activation of hPPAR ⁇ vs. hPPAR ⁇ differ by less than 2-fold as measured by the cell-based transactivation assay or cell-free co- activator association assay.
  • the compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ is orally active.
  • the compound that is capable of simultaneously binding and activating PPAR ⁇ and PPAR ⁇ possesses a long duration of action.
  • the inflammatory disease or condition is inflammatory bowel syndrome.
  • the inflammatory disease or condition is arthritis.
  • the inflammatory disease or condition is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, and juvenile arthritis.
  • concomitantly administering means administering one compound by a route and in an amount commonly used therefor, contemporaneously or sequentially with another compound.
  • a pharmaceutical composition in unit dosage form containing the two drugs is preferred
  • PPAR ⁇ agent means a compound that selectively binds or binds and activates PPAR ⁇ as defined above.
  • PPAR ⁇ agent means a compound that selectively binds or binds and activates PPAR ⁇ .
  • Utilities Compounds that are capable of simultaneously binding or simultaneously binding and activating PPAR ⁇ and PPAR ⁇ , or the concomitant use of selective PPAR ⁇ and PPAR ⁇ ligands/agonists, are useful for the treatment of inflammatory diseases or conditions.
  • the present invention encompasses the treatment of arthritis, including but not limited to rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • the invention also includes the treatment of: asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns and dermatitis; gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis; inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, vasculitis, systemic lupus erythematosis (SLE), Alzheimer's disease, atherosclerosis, acute respiratory distress syndrome (ARDS), myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, and myocardial isch
  • compositions of the present invention comprise a compound that is capable of simultaneously binding or simultaneously binding and activating PPAR ⁇ and PPAR ⁇ , or a combination of a selective PPAR ⁇ agent with a selective PPAR ⁇ agent, as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. In practical use, the present compounds can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. 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. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • 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 corn 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.
  • 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.
  • the present 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. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • 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.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N - dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • references to compounds capable of simultaneously binding or simultaneously binding and activating PPAR ⁇ and PPAR ⁇ are meant to also include the pharmaceutically acceptable salts thereof.
  • references to PPAR ⁇ agents or PPAR ⁇ agents are meant to include pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms.
  • the compounds encompassed by the present invention may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • the compounds encompassed by the present invention may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form, known as keto-enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of Formula II and Ha.
  • the compounds encompassed by the present invention may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of the compounds of the present invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • Any suitable route of administration may be employed for providing a mammal, and especially a human, with an effective dosage of the present compounds for the treatment of inflammatory diseases or conditions.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • the compounds are administered orally.
  • the effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compound When treating or preventing inflammatory diseases or conditions generally satisfactory results are obtained when the compound is administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, 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 compounds of the present invention for use in treating or preventing inflammatory diseases or conditions may be used in combination with other drugs for the treatment or prevention of inflammatory diseases or conditions.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound capable of simultaneously binding or simultaneously binding and activating PPAR ⁇ and PPAR ⁇ , or the combination of a selective PPAR ⁇ agents with a selective PPAR ⁇ agents with such other drug is preferred.
  • the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • examples of other active ingredients that may be combined with the present compounds for treating an inflammatory disease or condition, either administered separately or in the same pharmaceutical compositions include, but are not limited to:
  • a salicylate including acetylsalicylic acid
  • a non-steroidal antiinflammatory drug including indomethacin, sulindac, mefenamic, meclofenamic, tolfenamic, tolmetin, ketorolac, dicofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofin and oxaprozin
  • a cyclooxygenase-2 selective inhibitor such as rofecoxib, etoricoxib, celecoxib, parecoxib or valdecoxib
  • a corticosteroid including dexamethasone and prednisolone
  • TNF inhibitor including etanercept and infliximab
  • cytotoxic or immunosuppressive drug including methotrexate, leflunomide, azathioprine and cyclosporine, (8) a gold compound,
  • a p38 kinase inhibitor (13) an integrin ⁇ v antagonist, including the compounds disclosed in U.S. Patent No. 6,017,926 and U.S. Patent No. 6,048,861, and (14) a prostaglandin receptor ligand, such as the compounds disclosed in WO 00/20398, WO 99/47497 and WO 00/20371.
  • Expression constructs are prepared by inserting cDNA sequences encoding the ligand binding domains of human PPAR ⁇ or PPAR ⁇ adjacent to the yeast GAL4 transcription factor DNA binding domain in the mammalian expression vector pcDNA3 to create pcDNA3-hPPAR ⁇ /GAL4 and pcDNA3-hPPAR ⁇ /GAL4, respectively.
  • the GAL4-responsive reporter construct, pUAS(5X)-tk-luc contains 5 copies of the GAL4 response element 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.
  • COS-1 cells are seeded at 1.2 X 10 ⁇ cells/well in 96 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-
  • transfections are performed with Lipofectamine (Gibco-BRL, Gaithersburg, MD) according to the instructions of the manufacturer. Transfection mixes contain 0.00075 ⁇ g of PPAR ⁇ /GAL4 or PPAR ⁇ /GAL4 expression vector,
  • reporter vector pUAS(5X)-tk-luc 0.045 ⁇ g of reporter vector pUAS(5X)-tk-luc and 0.0002 ⁇ g of pCMV-lacZ vector as an internal control of transfection efficiency.
  • Compounds are characterized by incubation with transfected cells for 48h across a range of 8-12 concentrations from 0.1 nM to 50 uM.
  • Cell lysates are prepared from washed cells using Reporter Lysis Buffer (Promega) according to the manufacturer's directions.
  • Luciferase activity in cell extracts is determined using Luciferase Assay Buffer (Promega) in a ML3000 luminometer (Dynatech Laboratories), ⁇ -galactosidase activity is determined using ⁇ - D-galactopyranoside (Calbiochem-Novabiochem, LaJolla, CA) as described by Hollons and Yoshimura (Anal. Biochem, 182,411-418, 1989). Rosiglitazone can be used as a standard for human PPAR ⁇ activity. EC50 values for Rosiglitazone in the hPPAR ⁇ /GAL4 assay usually range from 20-40 nM. Fenofibrate can be used as a standard for hPPAR ⁇ activity.
  • EC50 values for Fenofibrate in the hPPAR ⁇ /GAL4 assay usually range from 5-20 uM.
  • methods involving the co-transfection of full-length PPAR ⁇ or PPAR ⁇ along with a relevant reporter gene into one of several mammalian (or yeast) cell types could be employed as an alternative method to identify compounds with both PPAR ⁇ and PPAR ⁇ agonist activity.
  • This assay measures the ability of compounds to promote the association of PPAR ⁇ (or its isolated ligand binding domain) or PPAR ⁇ (or its isolated ligand binding domain) with a protein (or portion of a protein) that is (or is derived from) a co-activator molecule such as Creb Binding Protein (CBP) or Steroid Receptor Coactivator 1 (SRC-1) and can be used to identify compounds with both PPAR ⁇ and PPAR ⁇ agonist activity.
  • CBP Creb Binding Protein
  • SRC-1 Steroid Receptor Coactivator 1
  • An alternative to measuring agonist activity of compounds in cell- based transactivation assays or cell-free co-activator association assays is to determine that compounds can function as ligands by binding to both PPAR ⁇ and PPAR ⁇ .
  • Compounds with half-maximal concentration potencies (ICso's or KI's) for displacement of radioligand binding to hPPAR ⁇ vs. hPPAR ⁇ that differ by less than 30-fold and preferably less than 10-fold can be considered as dual ligands.
  • Human PPAR ⁇ 2 and human PPAR ⁇ were expressed 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).
  • the full length human cDNA for PPAR ⁇ was subcloned into the pGEX-KT expression vector (Pharmacia).
  • E. coli containing the respective plasmids were propagated, induced, and harvested by centrifugation. The resuspended pellet was broken in a French press and debris was removed by centrifugation at 12,000Xg.
  • Recombinant human PPAR receptors were purified by affinity chromatography on glutathione sepharose. After application to the column, and one wash, receptor was eluted with glutathione. Glycerol (10%) was added to stabilize the receptor and aliquots were stored at -80 ° C.
  • TEGM 10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 ml ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 ⁇ g/mL aprotinin, 2 ⁇ g/mL leupeptin, 2 ⁇ g/mL benzamidine and 0.5 mM PMSF
  • 0.1% non-fat dry milk and 10 nM [-1H2] L-746,962, (21 Ci/mmole), ⁇ test compound.
  • a human PPAR ⁇ binding assay an aliquot of receptor 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 dithiothreitol, 5 ⁇ g/mL aprotinin, 2 ⁇ g/mL leupeptin, 2 ⁇ g/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 5.0 nM [3H2]L-783483, ⁇ test compound. Assays were incubated for TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 ml ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 ⁇ g/mL aprot
  • This assay is used for measuring the amount of MMP-9 secreted from cultured human monocytic THP-1 in response to lipopollysaccharide (LPS) stimulation.
  • LPS lipopollysaccharide
  • Cultured THP-1 cells were treated with PPAR ⁇ and/or ⁇ agonists for 2 hr at 37°C. The cells were then stimulated with bacteria LPS (1 ng/ml). After 48 hr incubation at 37°C, culture supernatants were collected. MMP-9 secreted in the media were measured by ELISA using antibodies specific to MMP-9.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding PPARα and PPARη or concomitantly administering a compound that selectively binds PPARα with a compound that selectively binds PPARη in an amount that is effective to treat or prevent the inflammatory disease or condition. The invention also encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding and activating PPARα and PPARη or concomitantly administering a compound that selectively binds and activates PPARα with a compound that selectively binds and activates PPARη in an amount that is effective to treat or prevent the inflammatory disease or condition.

Description

TITLE OF THE INVENTION
PPAR- ALPHA-GAMMA LIGANDS OR AGONISTS FOR THE TREATMENT OF
INFLAMMATION
BACKGROUND OF THE INVENTION
A key step in the process of inflammation is the ingress of leukocytes into inflammed tissue. During this process, the affected tissue responds to the inflammatory insult by the elaboration of cytokines, chemotactic factors, and adhesion molecules. These molecules serve in the attraction of leukocytes. Simultaneously, leukocytes respond to these factors by adhesion, migration, and elaboration of further cytokines and chemotactic factors. It is thus clear that inflammation requires the response of both the target tissue and the leukocytes. This dual contribution is illustrated by the failure of inflammation to occur in animals deficient in leukocyte adhesion molecules (beta-2 integrins) or in animals deficient in the tissue expression of the counterreceptor for integrins, ICAM-1. This invention involves administration of an agent that binds to transcription factors both in tissues and in leukocytes.
Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor supergene family. Three distinct PPARs, termed α, δ and γ, have been described. Each one is encoded by a separate gene. PPARs are characterized by distinct tissue distribution patterns and metabolic functions.
PPARγ is a transcription factor expressed in adipose tissues, cells of the colon, and in tissue macrophages. Several studies indicate that ligands for PPARγ suppress the expression of proinflammatory molecules (Nature 391:82, Nature 391;79: Cell 93, 241; Cell 93; 229 (1998)) and may have anti-inflammatory action in vivo (JCI 104: 383, 1999). It is noteworthy that strong anti-inflammatory activity was observed in a model of colon inflammation and PPARγ is strongly expressed in the colon. PPARα is a homologous transcription factor with a distinct expression pattern being present in liver, monocytes, smooth muscle cells and other tissues. Recent studies indicate that agonists of PPARα blunt production of pro-inflammatory cytokines (Nature 393: 790 (1998), Circulation 99: 3125 (1999)).
SUMMARY OF THE INVENTION
The invention encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding PPARα and PPARγ or concomitantly administering a compound that selectively binds PPARα with a compound that selectively binds PPARγ in an amount that is effective to treat or prevent the inflammatory disease or condition. The invention also encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding and activating PPARα and PPARγ or concomitantly administering a compound that selectively binds and activates PPARα with a compound that selectively binds and activates PPARγ in an amount that is effective to treat or prevent the inflammatory disease or condition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding PPARα and PPARγ or concomitantly administering a compound that selectively binds PPARα with a compound that selectively binds PPARγ in an amount that is effective to treat or prevent the inflammatory disease or condition.
Compounds that are capable of simultaneously binding PPARα and PPARγ or "dual ligands" are defined as those compounds with half-maximal concentration potencies (IC5θ's or KI's) for displacement of radioligand binding to hPPARγ vs. hPPARα that differ by less than 30-fold as measured by the human PPARα and PPARγ binding assays described below. All other compounds binding to PPARα and/or PPARγ that fall outside this definition are considered compounds that selectively bind either PPARα or PPARγ for purposes of this specification.
An embodiment of the invention encompasses administering the compound that is capable of simultaneously binding PPARα and PPARγ. An embodiment of the invention encompasses the instant method wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPARγ vs. hPPARα that differs by less than 20-fold as measured by the human PPARα and PPARγ binding assays. Another embodiment is wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPARγ vs. hPPARα that differs by less than 10-fold as measured by the human PPARα and PPARγ binding assays. Another embodiment is wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPARγ vs. hPPARα that differs by less than 5-fold as measured by the human PPARα and PPARγ binding assays. Another embodiment is wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for displacement of radioligand binding to hPPARγ vs. hPPARα differ by less than 2-fold as measured by the human PPARα and PPARγ binding assays.
Another embodiment of the invention encompasses the instant method wherein the compound that is capable of simultaneously binding PPARα and PPARγ is orally active. For purposes of this specification, compounds that are orally active means compounds that produce a therapeutic response following oral ingestion of the compound.
Another embodiment of the invention encompasses the instant method wherein the compound that is capable of simultaneously binding PPARα and PPARγ possesses a long duration of action. For purposes of this specification, compounds that possess a long duration of action means compounds that have a half-life equal to or exceeding about 1 hour.
Another embodiment of the invention encompasses the instant method wherein the inflammatory disease or condition is inflammatory bowel syndrome.
Another embodiment of the invention encompasses the instant method wherein the inflammatory disease or condition is arthritis. Within this embodiment is encompassed the instant method wherein the inflammatory disease or condition is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, and juvenile arthritis.
The compounds of the present invention that can be used in the treatment or prevention of an inflammatory disease or condition are compounds that have both PPARα and PPARγ activity, which are defined in terms of PPAR agonism or in terms of binding to the PPAR receptors, partially displacing other compounds that are excellent PPAR ligands. Another embodiment of the invention encompasses a method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding and activating PPARα and PPARγ or concomitantly administering a compound that selectively binds and activates PPARα with a compound that selectively binds and activates PPARγ in an amount that is effective to treat or prevent the inflammatory disease or condition.
Compounds that are capable of simultaneously binding and activating PPARα and PPARγ or "dual PPARα/PPARγ agonists" are defined as those compounds that exhibit both significant PPARα and PPARγ agonism as well as half- maximal concentration potencies (EC5θ's) for activation of hPPARγ vs. hPPARα that differ by less than 30-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay, which are described below. Compounds that exhibit both significant PPARα and PPARγ agonism are those compounds exhibiting >50% of the maximal effects of rosiglitazone (on human PPARγ) and >50% of the maximal effects of fenofibrate (on human PPARα) on both receptors as measured by the cell-based transactivation assay or cell-free co-activator association assay. It is these compounds that also exhibit half-maximal concentration potencies (ECso's) for activation of hPPARγ vs. hPPARα that differ by less than 30-fold that are considered "dual PPARα/PPARγ agonists" for purposes of this specification.
A compound that exhibits >50% of the maximal effects of rosiglitazone on human PPARγ but is outside the 30 fold activation difference described above is considered a compound that selectively binds and activates PPARγ. Rosiglitazone is an example of such a compound. Likewise, a compound that exhibits >50% of the maximal effects of fenofibrate on human PPARα but is outside the 30 fold activation difference described above is considered a compound that selectively binds and activates PPARα. Fenofibrate is an example of such a compound.
An embodiment of the invention encompasses administering the compound that is capable of simultaneously binding and activating PPARα and PPARγ.
Within this embodiment of the invention is encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half-maximal concentration potency (EC50) for activation of hPPARγ vs. hPPARα that differs by less than 20-fold as measured by the cell-based transactivation assay or cell-free co-activator association assay. Also within this embodiment is encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half- maximal concentration potency (EC50) for activation of hPPARγ vs. hPPARα that differs by less than 10-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay. Also within this embodiment is encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half-maximal concentration potency (EC50) for activation of hPPARγ vs. hPPARα that differs by less than 5-fold as measured by the cell-based transactivation assay or cell-free co-activator association assay. Also within this embodiment is encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half- maximal concentration potency (EC5θ's) for activation of hPPARγ vs. hPPARα differ by less than 2-fold as measured by the cell-based transactivation assay or cell-free co- activator association assay. Within this embodiment of the invention is also encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ is orally active. Also within this embodiment of the invention is encompassed the above method wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ possesses a long duration of action.
Also within this embodiment of the invention is encompassed the above method wherein the inflammatory disease or condition is inflammatory bowel syndrome.
Also within this embodiment of the invention is encompassed the above method wherein the inflammatory disease or condition is arthritis. Within this group is encompassed the above method wherein the inflammatory disease or condition is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, and juvenile arthritis.
For purposes of this specification "concomitantly administering" means administering one compound by a route and in an amount commonly used therefor, contemporaneously or sequentially with another compound. When compounds are referred to as administered concomitantly, a pharmaceutical composition in unit dosage form containing the two drugs is preferred
For purposes of this specification, a "PPARα agent" means a compound that selectively binds or binds and activates PPARα as defined above. "PPARγ agent" means a compound that selectively binds or binds and activates PPARγ.
Examples of compounds that are capable of simultaneously binding or simultaneously binding and activating PPARα and PPARγ, as well as examples of selective PPARα agents and selective PPARγ agents, are found in the following patents and published applications: WO 97/28115 published on August 7, 1997; WO 00/78312 published on December 28, 2000; WO 00/78313 published on December 28, 2000; U.S. No. 5,847,008 granted on December 8, 1998; U.S. No. 5,859,051 granted on January 12, 1999; U.S. No. 6,008,237 granted on December 28, 1999; U.S. No. 6,090,836 granted on July 18, 2000; U.S. No. 6,090,839 granted on July 18, 2000; U.S. No. 6,160,000 granted on December 12, 2000; and U.S. No. 6,200,998 granted on March 13, 2001, all of which are hereby incorporated by reference in their entirety.
Utilities Compounds that are capable of simultaneously binding or simultaneously binding and activating PPARα and PPARγ, or the concomitant use of selective PPARα and PPARγ ligands/agonists, are useful for the treatment of inflammatory diseases or conditions. For example, the present invention encompasses the treatment of arthritis, including but not limited to rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. The invention also includes the treatment of: asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns and dermatitis; gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis; inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, vasculitis, systemic lupus erythematosis (SLE), Alzheimer's disease, atherosclerosis, acute respiratory distress syndrome (ARDS), myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, and myocardial ischemia; ophthalmic diseases, such as retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and of acute injury to the eye tissue; and the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. Pharmaceutical Compositions
The pharmaceutical compositions of the present invention comprise a compound that is capable of simultaneously binding or simultaneously binding and activating PPARα and PPARγ, or a combination of a selective PPARα agent with a selective PPARγ agent, as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. In practical use, the present compounds can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. 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. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
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 corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When 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.
The present 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. In all cases, 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.
Salts
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N - dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, as used herein, references to compounds capable of simultaneously binding or simultaneously binding and activating PPARα and PPARγ are meant to also include the pharmaceutically acceptable salts thereof. Likewise, references to PPARα agents or PPARγ agents are meant to include pharmaceutically acceptable salts thereof. Optical Isomers - Diastereomers - Geometric Isomers - Tautomers
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms.
The compounds encompassed by the present invention may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. The compounds encompassed by the present invention may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula II and Ha. The compounds encompassed by the present invention may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
Alternatively, any enantiomer of the compounds of the present invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Administration and Dose Ranges
Any suitable route of administration may be employed for providing a mammal, and especially a human, with an effective dosage of the present compounds for the treatment of inflammatory diseases or conditions. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably the compounds are administered orally.
The effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating or preventing inflammatory diseases or conditions generally satisfactory results are obtained when the compound is administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, 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.
Combination Therapy
The compounds of the present invention for use in treating or preventing inflammatory diseases or conditions may be used in combination with other drugs for the treatment or prevention of inflammatory diseases or conditions. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound capable of simultaneously binding or simultaneously binding and activating PPARα and PPARγ, or the combination of a selective PPARα agents with a selective PPARγ agents with such other drug, is preferred. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with the present compounds for treating an inflammatory disease or condition, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:
(1) a salicylate, including acetylsalicylic acid, (2) a non-steroidal antiinflammatory drug, including indomethacin, sulindac, mefenamic, meclofenamic, tolfenamic, tolmetin, ketorolac, dicofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofin and oxaprozin, (3) a cyclooxygenase-2 selective inhibitor such as rofecoxib, etoricoxib, celecoxib, parecoxib or valdecoxib, (4) a corticosteroid, including dexamethasone and prednisolone
(5) a TNF inhibitor, including etanercept and infliximab,
(6) an IL-1 receptor antagonist,
(7) a cytotoxic or immunosuppressive drug, including methotrexate, leflunomide, azathioprine and cyclosporine, (8) a gold compound,
(9) hydroxychloroquine or sulfasalazine,
(10) penicillamine,
(11) darbufelone,
(12) a p38 kinase inhibitor, (13) an integrin αv antagonist, including the compounds disclosed in U.S. Patent No. 6,017,926 and U.S. Patent No. 6,048,861, and (14) a prostaglandin receptor ligand, such as the compounds disclosed in WO 00/20398, WO 99/47497 and WO 00/20371.
Biological Assays
Standardized Cell-Based GAL4 Chimeric Receptor Transactivation Assay (Cell- Based Transactivation Assay) The following assay is also described in: Berger J, Leibowitz MD,
Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas C, Cullinan CA, Hayes NS, Li Y, Tanen M, Ventre J, Wu MS, Berger GD, Mosley R, Marquis R, Santini C, Sahoo SP, Tolman RL, Smith RG, Moller DE. Novel peroxisome proliferator-activated receptory (PPARγ) and PPARδ ligands produce distinct biological effects, 1999 J Biol Chem 274: 6718-6725, herein incorporated by reference in its entirety:
Expression constructs are prepared by inserting cDNA sequences encoding the ligand binding domains of human PPARγ or PPARα adjacent to the yeast GAL4 transcription factor DNA binding domain in the mammalian expression vector pcDNA3 to create pcDNA3-hPPARγ/GAL4 and pcDNA3-hPPARα/GAL4, respectively. The GAL4-responsive reporter construct, pUAS(5X)-tk-luc, contains 5 copies of the GAL4 response element 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. COS-1 cells are seeded at 1.2 X 10^ cells/well in 96 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 μg/ml Streptomycin sulfate at 37°C in a humidified atmosphere of 10% CO2-
After 24 h, transfections are performed with Lipofectamine (Gibco-BRL, Gaithersburg, MD) according to the instructions of the manufacturer. Transfection mixes contain 0.00075 μg of PPARγ/GAL4 or PPARα/GAL4 expression vector,
0.045 μg of reporter vector pUAS(5X)-tk-luc and 0.0002 μg of pCMV-lacZ vector as an internal control of transfection efficiency. Compounds are characterized by incubation with transfected cells for 48h across a range of 8-12 concentrations from 0.1 nM to 50 uM. Cell lysates are prepared from washed cells using Reporter Lysis Buffer (Promega) according to the manufacturer's directions. Luciferase activity in cell extracts is determined using Luciferase Assay Buffer (Promega) in a ML3000 luminometer (Dynatech Laboratories), β-galactosidase activity is determined using β- D-galactopyranoside (Calbiochem-Novabiochem, LaJolla, CA) as described by Hollons and Yoshimura (Anal. Biochem, 182,411-418, 1989). Rosiglitazone can be used as a standard for human PPARγ activity. EC50 values for Rosiglitazone in the hPPARγ/GAL4 assay usually range from 20-40 nM. Fenofibrate can be used as a standard for hPPARα activity. EC50 values for Fenofibrate in the hPPARα/GAL4 assay usually range from 5-20 uM. Similarly, methods involving the co-transfection of full-length PPARγ or PPARγ along with a relevant reporter gene into one of several mammalian (or yeast) cell types could be employed as an alternative method to identify compounds with both PPARα and PPARγ agonist activity.
Cell-Free Co-Activator Association Assay
This assay measures the ability of compounds to promote the association of PPARγ (or its isolated ligand binding domain) or PPARα (or its isolated ligand binding domain) with a protein (or portion of a protein) that is (or is derived from) a co-activator molecule such as Creb Binding Protein (CBP) or Steroid Receptor Coactivator 1 (SRC-1) and can be used to identify compounds with both PPARα and PPARγ agonist activity. This assay is described in: Zhou G, Cummings R, Li Y, Mitra S, Wilkinson H, Elbrecht A, Hermes JD, Schaeffer JM, Smith RG, Moller DE. Nuclear receptors have distinct affinities for co-activators: characterization by fluorescence resonance energy transfer. Mol Endocrinol 1998 12:1594-1604, herein incorporated by reference in its entirety.
Human PPARα and PPARγ binding assays
An alternative to measuring agonist activity of compounds in cell- based transactivation assays or cell-free co-activator association assays is to determine that compounds can function as ligands by binding to both PPARγ and PPARα. Compounds with half-maximal concentration potencies (ICso's or KI's) for displacement of radioligand binding to hPPARγ vs. hPPARα that differ by less than 30-fold and preferably less than 10-fold can be considered as dual ligands. For these assays, the methods described below can be employed (as also described in: Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas C, Cullinan CA, Hayes NS, Li Y, Tanen M, Ventre J, Wu MS, Berger GD, Mosley R, Marquis R, Santini C, Sahoo SP, Tolman RL, Smith RG, Moller DE. Novel peroxisome proliferator-activated receptory (PPARγ) and PPARδ ligands produce distinct biological effects, 1999 J Biol Chem 274: 6718-6725, herein incorporated by reference in its entirety):
Human PPARγ2 and human PPARα were expressed as a GST-fusion protein in E. coli. The full length human cDNA for PPARγ2 was subcloned into the pGEX-2T expression vector (Pharmacia). The full length human cDNA for PPARα was subcloned into the pGEX-KT expression vector (Pharmacia). E. coli containing the respective plasmids were propagated, induced, and harvested by centrifugation. The resuspended pellet was broken in a French press and debris was removed by centrifugation at 12,000Xg. Recombinant human PPAR receptors were purified by affinity chromatography on glutathione sepharose. After application to the column, and one wash, receptor was eluted with glutathione. Glycerol (10%) was added to stabilize the receptor and aliquots were stored at -80 °C.
For each assay, an aliquot of receptor was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 ml β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamidine and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 10 nM [-1H2] L-746,962, (21 Ci/mmole), ± test compound. Assays were incubated for -16 hr at 4 °C in a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL dextran gelatin-coated charcoal, on ice, for 10 min. After centrifugation at 3000 rpm for 10 min at 4 °C, 50 μL of the supernatant fraction was counted in a Topcount. In this assay the KD for L-746,962 is ~ 1 nM.
For a human PPARα binding assay, an aliquot of receptor was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 ml β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 5.0 nM [3H2]L-783483, ± test compound. Assays were incubated for
-16 hr at 4 °C in a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL dextran gelatin-coated charcoal, on ice, for -10 min. After centrifugation at 3000 rpm for 10 min at 4 °C, 50 μL of the supernatant fraction was counted in a Topcount.
Cell Proliferation Assay This assay measures the ability of cells to convert MTS tetrazolium into formazan, using the AQue0us cell proliferation assay kit (Promega, Madison, WI). This conversion is presumably accomplished by NADPH or NADH produced by dehydrogenase enzymes in metabolically active cells. The assay is described in Shu, et al., Biochemical and Biophysical Research Communications, vol. 267, pp. 345-349 (2000).
MMP-9 ELISA
This assay is used for measuring the amount of MMP-9 secreted from cultured human monocytic THP-1 in response to lipopollysaccharide (LPS) stimulation. The assay is described in Shu, et al., Biochemical and Biophysical
Research Communications, vol. 267, pp. 345-349 (2000). Cultured THP-1 cells were treated with PPARα and/or γ agonists for 2 hr at 37°C. The cells were then stimulated with bacteria LPS (1 ng/ml). After 48 hr incubation at 37°C, culture supernatants were collected. MMP-9 secreted in the media were measured by ELISA using antibodies specific to MMP-9.
To demonstrate additive anti-inflammatory action of PPARα and PPARγ agents in combination or the action of a compound capable of simultaneously binding and activating PPARα and PPARγ, the release of a pro-inflammatory protein, MMP-9, in response to lipopolysaccharide (LPS) was measured. Dosing with PPARα and PPARγ agents together or with a dual PPARα/γ agent produces an unexpectedly superior decrease in the secretion of MMP-9 as compared to the either a PPARα or PPARγ agent alone.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding PPARα and PPARγ or concomitantly administering a compound that selectively binds PPARα with a compound that selectively binds PPARγ in an amount that is effective to treat or prevent the inflammatory disease or condition.
2. The method according to Claim 1 comprising administering the compound that is capable of simultaneously binding PPARα and PPARγ.
3. The method according to Claim 2 wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for the displacement of radioligand binding to hPPARγ vs. hPPARα that differs by less than 20-fold as measured by the human PPARα and PPARγ binding assays.
4. The method according to Claim 2 wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for the displacement of radioligand binding to hPPARγ vs. hPPARα that differs by less than 10-fold as measured by the human PPARα and PPARγ binding assays.
5. The method according to Claim 2 wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for the displacement of radioligand binding to hPPARγ vs. hPPARα that differs by less than 5-fold as measured by the human PPARα and PPARγ binding assays.
6. The method according to Claim 2 wherein the compound that is capable of simultaneously binding PPARα and PPARγ has a half-maximal concentration potency (IC50 or KI) for the displacement of radioligand binding to hPPARγ vs. hPPARα that differs by less than 2-fold as measured by the human PPARα and PPARγ binding assays.
7. The method according to Claim 2 wherein the compound that is capable of simultaneously binding PPARα and PPARγ that is capable of simultaneously binding PPARα and PPARγ is orally active.
8. The method according to Claim 2 wherein the compound that is capable of simultaneously binding PPARα and PPARγ possesses a long duration of action.
9. The method according to Claim 1 wherein the inflammatory disease or condition is inflammatory bowel syndrome.
10. The method according to Claim 1 wherein the inflammatory disease or condition is arthritis.
11. The method according to Claim 10 wherein the inflammatory disease or condition is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, and juvenile arthritis.
12. A method for treating or preventing an inflammatory disease or condition in a mammalian patient in need of such treatment or prevention comprising administering to said patient a compound that is capable of simultaneously binding and activating PPARα and PPARγ or concomitantly administering a compound that selectively binds and activates PPARα with a compound that selectively binds and activates PPARγ in an amount that is effective to treat or prevent the inflammatory disease or condition in accordance with Claim 1.
13. The method according to Claim 12 comprising administering the compound that is capable of simultaneously binding and activating PPARα and PPARγ.
14. The method according to Claim 13 wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half- maximal concentration potency (EC50) for activation of hPPARγ vs. hPPARα that differs by less than 20-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay.
15. The method according to Claim 13 wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half- maximal concentration potency (EC50) for activation of hPPARγ vs. hPPARα that differs by less than 10-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay.
16. The method according to Claim 13 wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half- maximal concentration potency (EC50) for activation of hPPARγ vs. hPPARα that differs by less than 5-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay.
17. The method according to Claim 13 wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ has a half- maximal concentration potency (EC50) for activation of hPPARγ vs. hPPARα that differs by less than 2-fold as measured by the cell-based transactivation assay or cell- free co-activator association assay.
18. The method according to Claim 13 wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ is orally active.
19. The method according to Claim 13 wherein the compound that is capable of simultaneously binding and activating PPARα and PPARγ possesses a long duration of action.
20. The method according to Claim 12 wherein the inflammatory disease or condition is inflammatory bowel syndrome.
21. The method according to Claim 12 wherein the inflammatory disease or condition is arthritis.
22. The method according to Claim 21 wherein the inflammatory disease or condition is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, gout, psoriasis, osteoarthritis, and juvenile arthritis.
EP02731386A 2001-04-18 2002-04-12 Ppar-alpha-gamma ligands or agonists for the treatment of inflammation Withdrawn EP1389044A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US28474701P 2001-04-18 2001-04-18
US284747P 2001-04-18
PCT/US2002/011990 WO2002085123A1 (en) 2001-04-18 2002-04-12 Ppar-alpha-gamma ligands or agonists for the treatment of inflammation

Publications (2)

Publication Number Publication Date
EP1389044A1 true EP1389044A1 (en) 2004-02-18
EP1389044A4 EP1389044A4 (en) 2006-07-05

Family

ID=23091378

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02731386A Withdrawn EP1389044A4 (en) 2001-04-18 2002-04-12 Ppar-alpha-gamma ligands or agonists for the treatment of inflammation

Country Status (4)

Country Link
EP (1) EP1389044A4 (en)
JP (1) JP2004528329A (en)
CA (1) CA2443935A1 (en)
WO (1) WO2002085123A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9133099B2 (en) 2005-07-22 2015-09-15 Nogra Pharma Limited Compounds and their salts specific to the PPAR receptors and the EGF receptors and their use in the medical field
US9511041B2 (en) 2009-02-16 2016-12-06 Nogra Pharma Limited Alkylamido compounds and uses thereof
US9682050B2 (en) 2012-04-18 2017-06-20 Nogra Pharma Limited Methods of treating lactose intolerance
US9913817B2 (en) 2008-12-05 2018-03-13 Nogra Pharma Limited Methods for preventing or reducing colon carcinogenesis
US11753365B2 (en) 2012-02-09 2023-09-12 Nogra Pharma Limited Methods of treating fibrosis
US11905232B2 (en) 2019-02-08 2024-02-20 Nogra Pharma Limited Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0127916D0 (en) * 2001-11-21 2002-01-16 Rowett Res Inst Method
PT2386310T (en) 2002-08-28 2019-02-05 Dyax Corp Methods for preserving organs and tissues
ES2272926T3 (en) * 2003-11-28 2007-05-01 Merck Sante HYPERURICEMIA TREATMENT.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6200998B1 (en) * 1997-12-19 2001-03-13 Merck & Co., Inc. Arylthiazolidinedione derivitives
WO2001025226A1 (en) * 1999-10-05 2001-04-12 Bethesda Pharmaceuticals, Inc. Dithiolane derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6200998B1 (en) * 1997-12-19 2001-03-13 Merck & Co., Inc. Arylthiazolidinedione derivitives
WO2001025226A1 (en) * 1999-10-05 2001-04-12 Bethesda Pharmaceuticals, Inc. Dithiolane derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RICOTE M ET AL: "THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-A IS A NEGATIVE REGULATOR OF MACROPHAGE ACTIVATION" NATURE, NATURE PUBLISHING GROUP, LONDON, GB, vol. 391, no. 6662, January 1998 (1998-01), pages 79-82, XP000906976 ISSN: 0028-0836 *
See also references of WO02085123A1 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9133099B2 (en) 2005-07-22 2015-09-15 Nogra Pharma Limited Compounds and their salts specific to the PPAR receptors and the EGF receptors and their use in the medical field
US9345680B2 (en) 2005-07-22 2016-05-24 Nogra Pharma Limited Compounds and their salts specific to the PPAR receptors and the EGF receptors and their use in the medical field
US9561202B2 (en) 2005-07-22 2017-02-07 Nogra Pharma Limited Compounds and their salts specific to the PPAR receptors and the EGF receptors and their use in the medical field
US9913817B2 (en) 2008-12-05 2018-03-13 Nogra Pharma Limited Methods for preventing or reducing colon carcinogenesis
US9511041B2 (en) 2009-02-16 2016-12-06 Nogra Pharma Limited Alkylamido compounds and uses thereof
US9901557B2 (en) 2009-02-16 2018-02-27 Nogra Pharma Limited Methods of treating hair related conditions
US10398667B2 (en) 2009-02-16 2019-09-03 Nogra Pharma Limited Methods of treating hair related conditions
US10959970B2 (en) 2009-02-16 2021-03-30 Nogra Pharma Limited Methods of treating hair related conditions
US11753365B2 (en) 2012-02-09 2023-09-12 Nogra Pharma Limited Methods of treating fibrosis
US9682050B2 (en) 2012-04-18 2017-06-20 Nogra Pharma Limited Methods of treating lactose intolerance
US11905232B2 (en) 2019-02-08 2024-02-20 Nogra Pharma Limited Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

Also Published As

Publication number Publication date
JP2004528329A (en) 2004-09-16
CA2443935A1 (en) 2002-10-31
WO2002085123A1 (en) 2002-10-31
EP1389044A4 (en) 2006-07-05

Similar Documents

Publication Publication Date Title
JP4368683B2 (en) 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
US9492439B2 (en) Amido compounds as RORγt modulators and uses thereof
KR100911073B1 (en) Crystal forms of an imidazole derivative
US20030032581A1 (en) Pharmaceuticals for treating obesity
AU2013358591B2 (en) Pyrimido [4,5-b]quinoline-4,5 (3H,10H)-diones as nonsense mutation suppressors
JP2005526040A (en) Use of cyclooxygenase inhibitors and antimuscarinic agents for the treatment of incontinence
JP2010526807A (en) Treatment using condensed aromatic compounds having anti-diabetic activity
PT92935B (en) METHOD FOR PREPARING A PYRAZOLE-PYRIDINE COMPOUND AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
WO2011112264A1 (en) Compounds as rorϒt modulators and uses thereof
TW201210585A (en) Phenylthioacetate compositions and methods of use
RU2338556C2 (en) Pharmaceutical composition, containing antagonist of p2x7-receptor and nonsteroid antiinflammatory medical product
EP1389044A1 (en) Ppar-alpha-gamma ligands or agonists for the treatment of inflammation
EP3152209B1 (en) Naphthyridinedione derivatives as suppressors of non-sense mutations
US20040115127A1 (en) Ppar-alpha-gamma ligands or agonists for the treatment of inflammation
US20210040098A1 (en) Apelin receptor agonists and methods of use thereof
EP3152208A1 (en) PYRIMIDO[4,5-b]QUINOLINE-4,5(3H,10H)-DIONE DERIVATIVES
AU2002303366A1 (en) Ppar-alpha-gamma ligands or agonists for the treatment of inflammation
US20040248863A1 (en) Combination of a ppar-alpha ligand and glucocorticoid for the treatment or prevention of inflamation
JP7277676B2 (en) pyrimidine derivative
US20040116327A1 (en) Use of ppar-alpha-gamma ligands or agonists to prevent the rupture of atherosclerotic plaques
AU764875B2 (en) Combination of a GABA-A alpha 5 inverse agonist and COX-2 inhibitor, NSAID, estrogen or vitamin
AU2002256250A1 (en) Use of ppar-alpha-gamma ligands or agonists to prevent the rupture of atherosclerotic plaques
US20040167107A1 (en) Ppar-alpha ligands for the treatment or prevention of cachexia
Folco Inhibitors of leukotrienes: An overview
US10399946B2 (en) Solid forms of an S-Nitrosoglutathione reductase inhibitor

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031118

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

A4 Supplementary search report drawn up and despatched

Effective date: 20060606

17Q First examination report despatched

Effective date: 20060808

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20061219