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WO2002013812A1 - Traitements de maladies inflammatoires - Google Patents

Traitements de maladies inflammatoires Download PDF

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Publication number
WO2002013812A1
WO2002013812A1 PCT/US2001/025668 US0125668W WO0213812A1 WO 2002013812 A1 WO2002013812 A1 WO 2002013812A1 US 0125668 W US0125668 W US 0125668W WO 0213812 A1 WO0213812 A1 WO 0213812A1
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disease
pparγ
insulin
agonist
sensitizing agent
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PCT/US2001/025668
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English (en)
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Harrihar A. Pershadsingh
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Pershadsingh Harrihar A
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Priority to AU2001288271A priority Critical patent/AU2001288271A1/en
Publication of WO2002013812A1 publication Critical patent/WO2002013812A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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
    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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

Definitions

  • This invention relates to use of PPAR (peroxisome proliferator-activated receptor)- ⁇ ligands belonging to the group consisting of: 1) a pure PPAR ⁇ agonist, 2) a PPAR ⁇ agonist that also activates PPAR ⁇ (PPAR ⁇ /PPAR ⁇ dual agonist), 3) a PPAR ⁇ agonist that also activates PPAR ⁇ (PPAR ⁇ /PPAR ⁇ dual agonist), 4) a PPAR ⁇ agonist that also activates both PPAR ⁇ and PPAR ⁇ (PPAR "pan-agonist”), 5) a PPAR ⁇ partial agonist, 6) a PPAR ⁇ /RXR agonist, leading to the transcription of its target genes controlled by these nuclear transcription factors.
  • PPAR peroxisome proliferator-activated receptor
  • This invention relates to the uses of said ligands to treat diseases of multiple organ systems, including those contained in the cardiovascular system, integumentary system, skeletal system (cartilage and bone), bone marrow (myeloid and erythroid progenitor cells and cell lines), the immune system (including spleen, thymus, lymph nodes, Peyer's patch), central and peripheral nervous system, endocrine glands, exocrine glands, urogenital system, gastrointestinal system and pulmonary system.
  • diseases and conditions that lead to impaired health derive from hereditary (genetic) or environmental insults (e.g.
  • PPAR isoforms are selectively (differentially) expressed in different tissues, to different degrees (amounts expressed) and operationally intact (physiologically functional), the treatment of multigenic diseases require that the targeting ligand also be functionally pleiotropic in order to address the heterogenous components of these diseases.
  • Hypertension, diabetes, congestive heart failure, psoriasis, atherosclerosis, dementia, demyelinating diseases, atopy, and the aging process are examples of such diseases and conditions.
  • this principle may be applied to isoform subtypes as in the case of the PPAR ⁇ subtypes, PPAR ⁇ 1, PPAR ⁇ 2 and PPAR ⁇ 3.
  • the present invention relates to the development of compounds for the treatment (i.e. prevention, amelioration, attenuation, arrest or reversal) of a PPAR-dependent disease or condition.
  • the disease process or condition may be associated with inappropriate expression of PPARs or dysfunctional PPARs.
  • the pathology may be related to disruption(s) in signaling pathways of hormones, neurotransmitters or other informational molecules, wherein the PPAR target(s) is (are) intact. Consequently, ligands may be designed for repairing pathological lesions proximal to the PPARs or at the level of PPARs and their interaction with receptor co-activators and/or co-repressors.
  • application of this invention relates to the treatment (prevention, amelioration, attenuation, arrest or reversal) of "non-pathological" (non-life-threatening) conditions such as natural (normal) aging of organs and tissues conditions.
  • methods relating to this aspect of the invention include preventing inappropriate tissue modeling through inappropriate expression of matrix metalloproteinases (MMPs) on the one hand, and promoting appropriate expression of matrix proteins such as collagen, laminin, elastin, proteoglycans, and tissue inhibitors of MMPs (TIMPs) on the other.
  • MMPs matrix metalloproteinases
  • TMPs tissue inhibitors of MMPs
  • the PPARs consist of three closely related nuclear receptors, PPAR ⁇ , PPAR ⁇ , PPAR ⁇ , encoded by three separate genes, and comprise a subfamily within the broader nuclear receptor superfamily (Mangelsdorf DJ, Evans RM. Cell 1995; 83:841-50).
  • Nuclear receptors like PPAR possess DNA binding domains (DBDs) that recognize specific DNA sequences (called response elements) located in the regulatory regions of their target genes (see, Mangelsdorf, et al. Cell 83:835-839 (1995)); Perlmann, et al.
  • PPARs perixosome proliferator response elements
  • the three PPARs share about 80% and about 70% amino acid identity in their DBDs and ligand binding domains (LBDs), respectively.
  • PPAR ⁇ the first PPAR to be cloned, is most highly expressed in the liver, kidney, heart, and muscle, and is activated by peroxisome proliferators, a structurally diverse group of compounds which includes fibrates, herbicides, and phthalate ester plasticizers (Reddy JK, Lalwai ND. Crit. Rev. Toxicol.
  • PPAR ⁇ is the target for the fibrate class of hypolipidemic drugs, such as clofibrate, fenofibrate, and bezafibrate, which are used to lower triglycerides and raise HDL-cholesterol in dyslipidemic patients.
  • hypolipidemic drugs such as clofibrate, fenofibrate, and bezafibrate
  • PPAR/RXR heterodimers are permissive in that they can be activated by ligands for either PPAR or RXR.
  • PPARs PPARs. These subtle differences in binding specificity together with the differences in tissue expression patterns undoubtedly contribute to the distinct physiological roles of the three PPAR subtypes. In contrast to PPAR ⁇ , relatively little is known about the biology of PPAR ⁇ , which is expressed at comparable levels in virtually all tissues. All three PPAR subtypes bind to DNA as obligate heterodimers with RXR ⁇ , RXR ⁇ , or RXR ⁇ , the nuclear receptors for 9- cis-retinoic acid. In this respect, this invention specifically relates to the ligands of the PPAR ⁇ /RXR heterodimer.
  • PPAR ⁇ is unique in that three different PPAR ⁇ transcripts, termed PPAR ⁇ 1, PPAR ⁇ 2 and PPAR ⁇ 3, have been described, and are derived from the PPAR ⁇ gene by differential promoter usage.
  • PPAR ⁇ l is broadly expressed at moderate or low levels in almost all tissues, while PPAR ⁇ 2, is restricted to adipose (white fat and brown fat) tissue and large gut, and PPAR ⁇ 3 is confined to adipose tissue, macrophages and colonic epithelium in human tissues PPAR ⁇ l is broadly expressed, albeit at low levels.
  • PPAR ⁇ 2 and PPAR ⁇ 3 are highly expressed in adipose tissue, and PPAR ⁇ 3 is also expressed in macrophages (Mangelsdorf DJ, Evans RM. Cell 1995;83:841-850; Spiegelman BM. Diabetes 1998;47:507-514; Willson TM, et al. J Med Chem 2000; 43:527-550).
  • PPAR ⁇ refers to PPAR ⁇ l, PPAR ⁇ 2 or PPAR ⁇ 3, or combination thereof.
  • PPAR ⁇ is functionally involved in intermediary metabolism of cells and tissues expressed therein.
  • the PPARs are differentially expressed in different organs and tissues.
  • PPAR ⁇ and PPAR ⁇ tend to be ubiquitously expressed in most tissues.
  • PPAR ⁇ is most highly expressed fetal tissue, placenta and in the brain and CNS, and may control differentiation in these tissues.
  • Activation of PPARs modulate expression of genes involved in: 1) intermediary (e.g. glucose and lipid) metabolism, 2) regulation of mitosis and cell growth, 3) regulation of blood vessel growth (neovascularization), 4) regulation of cellular differentiation and phenotype transition, 5) immunoregulation (e.g.
  • PPARs are remarkably promiscuous in their ligand binding properties.
  • the molecular basis of this promiscuity is the presence of a large hydrophobic ligand binding site, more than 1000 A 3 in size.
  • PPAR ⁇ agonists are insulin-sensitizing agents which also promote adipocyte differentiation and adipogenesis with consequent weight gain.
  • Stabilization of the AF-2 helix leads to activation of the genetic program for adipocyte differentiation and fat accumulation.
  • a ligand capable of binding with high affinity to PPAR ⁇ without stabilizing the AF2 helix (Willson TM, et al. J Med Chem 2000; 43:527-550).
  • An example of such a "partial agonist" is the compound, GW0072 inhibits adipocyte differentiation and adipogenesis but retains insulin-sensitizing, antidiabetic activity in animal models (Willson TM, et al. Annu Rev Biochem 2001; 70:341-367).
  • PPAR agonists have been shown to inhibit the expression of inflammatory cytokines such as TNF- ⁇ , IL-1, IL-2, IL-6 in cells of the immune system including, T lymphocytes, B lymphocytes, monocytes, monocyte/macrophages, and splenocytes, and to suppress inflammation mediated by Thl lymphocytes (Marx N, et al. J Immunol 2000;164:6503; Padilla J, et al. Ann N Y Acad Sci 2000;905:97; Clark RB, et al. J Immunol 2000;164:1364; Yang XY, et al. J Biol Chem 2000;275:4541). PPAR agonists has also been shown to inhibit proliferation and promote differentiation of a variety of normal and neoplastic cell types.
  • 15d-PGJ2 was shown to be a potent inhibitor of cytokine production in monocytes or macrophages.
  • the potent PPAR ⁇ agonist, AD-5075 (5-[4-[2-(5-methyl-2- phenyl-4-oxazoly)-2-hydroxyethoxy]benzyl]-2,4-thiazolidinedione), and non- thiazolidinedione PPAR ⁇ /PPAR ⁇ /PPAR ⁇ pan-agonist, L-796,449 (3-chloro-4-(3-(3-phenyl-7- propylbenzofuran-6-yloxy)propylthio)-phenylacetic acid), failed to suppress TNF- ⁇ and IL-6 cytokine production in lipopolysaccharide-treated mice (Thieringer R, et al. Immunol 2000; 164:1046-54).
  • PPAR ⁇ agonists including 15d-PGJ2 and rosiglitazone, blocked cytokine production equally well in macrophages derived from either PPARy+/+ or PPAR ⁇ -I- embryonic stem cells (Chawla A, et al. Nat Med 2001 ; 7:48-52).
  • activators of both PPAR ⁇ and PPAR ⁇ agonists have been shown to inhibit or downregulate inflammatory molecules such as IL-2, inducible nitric oxide synthase (iNOS), and the proinflammatory nuclear transcription factors, NF- ⁇ B, AP-1, NFAT and STAT1.
  • T lymphocyte activation is highlighted by the induction of IL-2 gene expression, which governs much of the early lymphocyte proliferation responses.
  • IL-2 production proliferation in human peripheral blood T-cells The effect was evident only in T lymphocyte cell lines expressing PPAR ⁇ and not the PPAR ⁇ -lacking cells.
  • the activated PPAR ⁇ physically associates with transcriptional factor NFAT regulating the IL-2 promoter, blocking NFAT DNA binding and transcriptional activity. This interaction indicates an important immunomodulatory role for PPAR ⁇ ligands as immunotherapeutic drugs to treat T cell-mediated diseases by targeting IL-2 gene expression (Yang XY, et al. J Biol Chem 2000; 275:4541-4544).
  • This invention proposes that, by unknown and unpredictable mechanisms, ligand- activation of PPAR ⁇ , and PPAR ⁇ /RXR, through interactions with other nuclear factors, co- activators, co-repressors and components of immunomodulatory networking and signaling pathways, may be useful as therapeutic immunomodulating agents.
  • the present invention generally relates to the treatment of T lymphocyte-related diseases that involve activation of NFAT, NF- ⁇ B or AP-1, inappropriate activation of nuclear transcription factors that regulate the transcription of genes encoding inflammatory cytokines, and inappropriate transcription of disease-dependent target genes.
  • immunomodulatory cytokines examples include, interferon- ⁇ (INF ⁇ ), tumor necrosis factor- ⁇ (TNF- ⁇ ), IL-l ⁇ , IL-2, IL-6, IL- 8, IL-10 (Chinetti G, et al. J Biol Chem 1998; 273:25573-25580; Escher P, Wahli W. Mutat Res 2000; 448:121-138; Ricote M, et al. J Leukoc Biol 1999; 66:733-739; Rocchi S, Auwerx J. Ann Med 1999; 31:342-351).
  • This invention further relates to the prevention or treatment of disorders of inflammatory and immunomodulatory responses of the immune system involving: T helper (T JJ ), T suppressor (T s ), Thl and Th2 lymphocytes, natural killer (NK) and other T cell subsets.
  • T JJ T helper
  • T s T suppressor
  • Thl and Th2 lymphocytes Thl and Th2 lymphocytes
  • NK natural killer
  • the methods described in this invention relates to an improvement in the prior art, related to superior efficacy of recruiting co-activators and/or co-repressors in order to optimize the activation or inactivation of the various PPAR isoforms in the treatment or prevention of a particular disease involving, for example: 1) promoting apoptosis in cells with the pathological phenotype, 2) blockade of inappropriate apoptosis induction in normal cells triggered by inflammatory molecules, in particular IL-2, and pro-inflammatory nuclear transcription factors, in particular NF- ⁇ B, as in neurodegenerative diseases (Alzheimer's disease) and autoimmune diseases (multiple sclerosis), 3) inhibiting systemic inflammation by suppressing Thl -mediated inflammatory cytokines and promoting Thl to Th2 phenotypic transition, leading to treatment or prevention diseases such as atherosclerosis, syndrome X and congestive heart failure.
  • a particular disease involving, for example: 1) promoting apoptosis in cells with the pathological
  • PPAR ligands specifically a PPAR ⁇ agonist which cross- activates PPAR ⁇ or PPAR ⁇ or both, or a partial PPAR ⁇ agonist, or a PPAR ⁇ /RXR ligand are: inflammatory skin diseases (e.g. psoriasis, atopic dermatitis, eczema, acne vulgaris, and other dermatitides), neurodegenerative diseases (e.g. multiple sclerosis, Alzheimer's disease, Parkinson's disease), cardiovascular diseases (e.g.
  • inflammatory skin diseases e.g. psoriasis, atopic dermatitis, eczema, acne vulgaris, and other dermatitides
  • neurodegenerative diseases e.g. multiple sclerosis, Alzheimer's disease, Parkinson's disease
  • cardiovascular diseases e.g.
  • the immune system includes T lymphocytes, B lymphocytes, monocytes, macrophages, monocyte/macrophages, macrophage-like cells (e.g.
  • astrocytes in the brain retinal pigmented epithelial cells in the retina
  • cells of myeloid origin in any tissue in particular the bone marrow (stem cells, pre-promyelocytes, promyelocytes, myelocytes, granulocytes, plasma cells, mast cells, basophils, polymorphonuclear cells, eosinophils).
  • stem cells pre-promyelocytes, promyelocytes, myelocytes, granulocytes, plasma cells, mast cells, basophils, polymorphonuclear cells, eosinophils.
  • phosphorylation could alter interactions with important, as yet undefined, protein cofactors of PPAR ⁇ which act as corepressors or coactivators.
  • nuclear receptors function as "ligand-gated” platforms for the assembly of these cofactors into large protein complexes on specific DNA sequences (Spiegelman BM. Diabetes 1998; 47:507-514).
  • Some of these coactivator proteins CBP/p300, SRC1, pCAF
  • CBP/p300, SRC1, pCAF have histone acetyltransferase activity that functions to "open” the configuration of chromatin, allowing more efficient transcription.
  • Others act as deacetylases which oppose the effects of acetyltransferases. Similar arguments apply to PPAR ⁇ and PPAR ⁇ modulation of gene transcription.
  • Thiazolidinediones are a class of oral insulin-sensitizing agents that improve glucose utilization without stimulating insulin release, are class of PPAR agonists.
  • U.S. Patent No. 4,287,200 discloses certain thiazolidine derivatives having the ability to lower blood glucose levels.
  • U.S. Patent No. 4,572,912 discloses thiazolindinedione derivatives having the ability to lower blood lipid and blood glucose levels. These compounds were shown to have the ability to decrease the levels of blood lipid peroxides, blood triglycerides and blood cholesterol.
  • a PPAR ⁇ ligand that binds with high affinity but which inhibits adipocyte differentiation and adipogenisis while retaining its insulin- sensitizing activity is a PPAR ⁇ partial agonist (Oberfield, et al, Proc Natl Acad Sci USA 96:6102-6 (1999)).
  • PPAR ⁇ partial agonists may dissociate the antidylipideniic effects from the drug's propensity for peroxisome proliferation, thereby have the benefit of improving lipid metabolism with out the risk of hepatitis or myositis, established adverse effects of PPAR ⁇ agonists such as the anti-dyslipidemic fibrates.
  • PPAR receptors also play a role in other processes. Binding of ligands to PPARs induce changes in the transcriptional activity of genes that modulate inflammatory processes, angiogenesis, cellular proliferation and differentiation, apoptosis, and the activities of iNOS, MMPases and TIMPs. These findings suggest that regulation of the action of PPAR may have a therapeutic role in treating diseases such as occlusive vascular diseases (e.g. atherosclerosis), hypertension, neovascular diseases (e.g. diabetic retinopathy), inflammatory diseases (e.g. inflammatory bowel disease and psoriasis), and neoplastic diseases (carcinogenesis).
  • diseases such as occlusive vascular diseases (e.g. atherosclerosis), hypertension, neovascular diseases (e.g. diabetic retinopathy), inflammatory diseases (e.g. inflammatory bowel disease and psoriasis), and neoplastic diseases (carcinogenesis).
  • DNA response elements for both PPAR ⁇ and PPAR ⁇ have been found in the promoter regions of a variety of genes, including a number involved in lipid and fatty acid metabolism. For example, in fetal rat brown adipocytes, expression of the uncoupling proteins UCP-1, UCP-2 and UCP-3 is controlled via both PPAR ⁇ and PPAR ⁇ activation. Activation of PPAR ⁇ elicited 5- and 3- fold increases in
  • PPAR ⁇ and PPAR ⁇ -related activity and mechanisms as well as the differential expression of PPAR ⁇ and PPAR ⁇ in cells, it is difficult to ascertain the potential effects of concurrent activation of PPAR ⁇ and ⁇ receptors on both cellular processes relevant to disease.
  • PPAR ⁇ or PPAR ⁇ may either have similar or disparate effects. It is known that inflammatory activation of human aortic smooth-muscle cells is inhibited by PPAR ⁇ , but not by PPAR ⁇ .
  • Apoptosis in human monocyte-derived macrophages is induced by activation of either PPAR ⁇ and PPAR ⁇ (see, Staels et al Nature 393:790-3 (1998)); Chinetti, et al. JBiol Chem. 273:25573-80 (1998)).
  • PPAR ⁇ activation by troglitazone or 15-deoxy- ⁇ -12-14-prostaglandin J2 protects cerebellar granule cells from cytokine-induced apoptotic cell death (see, Heneka, et al. J Neuroimmunol 100:156-68 (1999)).
  • PPAR isoforms exhibit differential patterns of tissue expression, different actions on different response elements, differential effects on co-activators and corepressors, and differential regulation of access to the core transcriptional machinery.
  • This complexity of PPAR regulation makes it extremely difficult to predict precisely which genes will ultimately be activated (transcribed) or inactivated (suppressed) as a result of activation by a particular combination of an agonist or an antagonist of PPAR ⁇ or PPAR ⁇ .
  • PPAR ⁇ and PPAR ⁇ may respond to a particular ligand, or whether a particular pathological state will be attenuated, arrested, accentuated or worsened by said ligand. This is especially the case in which a single ligand activates both PPAR ⁇ and PPAR ⁇ to similar degrees.
  • PPAR ⁇ and PPAR ⁇ activation has been shown to inhibit proliferation (see, Ellis, et al. Arch Dermatol.
  • PPAR ⁇ +/- mice were partially resistant to weight gain when placed on a high-fat diet that caused adipocyte hypertrophy and obesity in their wild-type littermates. PPARy +/- mice were also protected from the insulin resistance that accompanied weight gain in the wild-type animals. Therefore, the PPARy +/- phenotype may be pharmacologically induced in the wild-type by treatment with a PPAR ⁇ partial agonist.
  • a pharmaceutically acceptable ligand selected from the group consisting of: 1) a PPAR ⁇ agonist which cross-activates PPAR ⁇ (a PPAR ⁇ /PPAR ⁇ dual agonist), 2) a PPAR ⁇ agonist which cross-activates PPAR ⁇ (a PPAR ⁇ /PPAR ⁇ dual agonist), 3) a PPAR ⁇ partial agonist, 4) a PPAR ⁇ /RXR agonist, effective to reverse, slow, stop, or prevent the pathological inflammatory or degenerative process.
  • a pharmaceutically acceptable ligand selected from the group consisting of: 1) a PPAR ⁇ agonist which cross-activates PPAR ⁇ (a PPAR ⁇ /PPAR ⁇ dual agonist), 2) a PPAR ⁇ agonist which cross-activates PPAR ⁇ (a PPAR ⁇ /PPAR ⁇ dual agonist), 3) a PPAR ⁇ partial agonist, 4) a PPAR ⁇ /RXR agonist, effective to reverse, slow, stop, or prevent the pathological inflammatory or degenerative
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or derivative thereof, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier.
  • the present invention relates to a method of treating a PPAR- mediated inflammatory disease, comprising administering a therapeutically effective amount of a compound of the present invention or mixtures thereof to an individual suffering from a PPAR-mediated inflammatory disease.
  • PPAR ⁇ peroxisome proliferator activating receptor- ⁇
  • PPAR ⁇ refers to either the ⁇ l, ⁇ 2 or ⁇ 3 isotypes or a combination of all isotypes of PPAR ⁇ .
  • PPARs are nuclear receptors which naturally bind to fatty acids and which have been implicated in adipocyte differentiation (see, Perlmann et al. , Cell, 90:391-397 (1997)).
  • EC50 refers to the concentration of a compound required to activate 50% of the receptors that bind the compound present in a sample or a subject.
  • the EC50 of a PPAR ⁇ modifier is the concentration of the modifier that activates 50% of the PPAR ⁇ present in the sample or organism.
  • activate has its ordinary meaning, i. e. , cause to function or act.
  • agonist applies to a compound (ligand) that specifically binds and activates its target (cognate) receptor.
  • a PPAR ⁇ agonist specifically binds and activates all aspects of the PPAR ⁇ isoform.
  • a PPAR ⁇ agonist (“full” agonist) specifically binds PPAR ⁇ and activates downstream expression of a specific pattern of genes.
  • Each isoform e.g. PPAR ⁇ , PPAR ⁇ or PPAR ⁇
  • Each isoform e.g. PPAR ⁇ , PPAR ⁇ or PPAR ⁇
  • partial agonist applies to a compound (ligand) that specifically binds and partially activates its target (cognate) receptor. Partial activation refers to differential activation or incomplete activation, resulting in a different downstream gene expression pattern, compared to pattern triggered by an full agonist.
  • the compound GW0072 is a PPAR ⁇ partial agonist which binds to PPAR ⁇ with high affinity, but only partially activates the receptor. "Full" activation of PPAR ⁇ (e.g.
  • a PPAR ⁇ agonist promotes adipogenesis and differentiation of pre- adipocytes into mature adipocytes (terminal differentiation) and produces insulin-sensitization in vivo
  • partial activation of PPAR ⁇ by exposure to GW0072 inhibits adipogenesis and differentiation of adipocytes without affecting the compound's insulin-sensitizing effects, in vivo.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specifications for the unit dosage forms of this invention are dictated by and dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals.
  • unit dosage forms are tablets, capsules, pills, powder packets, wafers, suppositories, granules, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampoules, vials, aerosols with metered discharges, segregated multiples of any of the foregoing, and other forms as herein described.
  • cervical cancer includes the neoplasm at the primary site (cervix) and metastatic cervical cancer, regardless of site of metastasis, such as skeleton, brain, etc.
  • inflammatory disease includes diseases (treatable or preventable with compounds described in this invention) including, but not limited to, a. T-lymphocyte activation and other T-lymphocyte-related disorders. b. diseases involving the pathological production of inflammatory cytokines (e.g.
  • TNF- ⁇ interleukin (IL)-l ⁇ , IL-2, IL-6) c. activation of nuclear factors that promote transcription of genes encoding inflammatory cytokines.
  • nuclear transcription factors include but are not restricted to: nuclear factor- ⁇ B (NF- B), activated protein- 1 (AP-1), nuclear factor of activated T cells (NFAT).
  • diabetes refers to all variant forms of diabetes mellitus (DM), including type 1 DM, type 2 DM, gestational diabetes, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a PPAR ⁇ agonist which cross-activates PPAR ⁇ , a PPAR ⁇ agonist which cross-activates PPAR ⁇ , or a PPAR ⁇ agonist which cross-activates both PPAR ⁇ and PPAR ⁇ , or a PPAR ⁇ partial agonist, or a PPAR ⁇ /RXR agonist, derivatives thereof, their pharmaceutically acceptable salts or solvates thereof, compounded with a pharmaceutically acceptable carrier.
  • the compounds, composition and methods of the present invention can be used to treat diseases involving tissues that express PPAR ⁇ , PPAR ⁇ and PPAR ⁇ , and more particularly, can be used for treating inflammatory, proliferative, degenerative diseases of multiple organs and tissues, and diseases involving pathological angiogenesis and neovascularization.
  • the compounds can be used for treatment of diseases, tissues and organs regardless of etiological agent.
  • the treatment of corneal injury or ulceration caused by unrelated etiological agents is possible; these include, but are not limited to: 1) foreign body (e.g. contact lens), infectious agent (e.g.
  • physical agent e.g. UV radiation
  • chemical agent e.g. acids, caustic solvents
  • chronic systemic disease e.g. autoimmune or collagen vascular diseases.
  • Methods of the present invention for treating these inflammatory diseases comprise the administration of an effective amount of any natural or synthetic substance that modifies the activity of PPAR ⁇ , PPAR ⁇ , PPAR ⁇ , or PPAR ⁇ /RXR.
  • the methods of treatment are practiced by administering to a human in need thereof a dose of a compound (or pharmaceutically acceptable salts and solvates thereof in acceptable pharmaceutical excipients) that modifies the activity of PPAR ⁇ .
  • modifies and modulate are defined to include its usually accepted meaning and includes treating a human subject prophylactically to alter inflammation, apoptosis, proliferation, angiogenesis, neovascularization, immune dysfunction, and expression of oncogenes and other genes controlling cell metabolism.
  • the present method includes both medical therapeutic and/or prophylactic treatment, as necessary.
  • the compounds and methods described herein have clinical utility in the treatment of dermatological diseases (Table I), psychiatric disorders (Table II), neurodegenerative diseases (Table III), diseases associated with allograft transplantation (Table IV), inflammatory or degenerative diseases in multiple organ systems (Table V), neoplastic diseases (Table Via, Table VIb), diseases caused by naked or coated DNA and RNA viruses (Table VII), diseases associated with human immunodeficiency virus (HIV) infection (Table VIII), inflammatory, proliferative and degenerative diseases of the eye (Tables IXa, IXb, IXc, IXd, IXe), and conditions associated with injury and age-related dysregulations (Table X).
  • the methods of the present invention are practiced by administering to a mammal a dose of a compound, or a pharmaceutically acceptable salt, ester, solvate or tautomer thereof, a therapeutic amount that activates PPAR ⁇ and/or PPAR ⁇ .
  • a compound or a pharmaceutically acceptable salt, ester, solvate or tautomer thereof.
  • the specific diseases and associated disorders that can be treated with the compounds are listed in Tables I through X.
  • therapeutic compounds are typically administered to human patients topically to the skin or mucous membranes, by extra-ocular application, intraocularly (by chemical delivery system or invasive device), or systemically (e.g.
  • compositions are administered in unit dosage forms suitable for single administration of precise dosage amounts.
  • a therapeutically effective concentration of the compound is placed in a dermatological vehicle as is known in the art.
  • the amount of the therapeutic compound to be administered and the compound's concentration in the topical formulations depend upon the vehicle, delivery system or device selected, the clinical condition of the patient, the side effects and the stability of the compound in the formulation.
  • the physician employs the appropriate preparation containing the appropriate concentration of the therapeutic compound and selects the amount of formulation administered, depending upon clinical experience with the patient in question or with similar patients.
  • the therapeutic compound is optionally administered topically by the use of a transdermal therapeutic system (see, Barry, Dermatological Formulations, p. 181 (1983) and literature cited therein). While such topical delivery systems have been designed largely for transdermal administration of low molecular weight drugs, by definition they are capable of percutaneous delivery. They can be readily adapted to administration of the therapeutic compounds of the invention by appropriate selection of the rate-controlling microporous membrane.
  • the therapeutic compound is formulated into solutions, suspensions, and ointments appropriate for use in the eye.
  • concentrations are usually as discussed above for topico-local preparations.
  • the concentration of the therapeutic compound used depends on the mode of delivery. For topical ophthalmic and extraocular formulations, the concentration of the therapeutic compound is in the range of about 0.01% weight/weight (w/w) to about 10% w/w. Typically, the concentration of the therapeutic compound for this mode of delivery is in the range of about 0.025% w/w to about 2.5% w/w. Solid dispersions of the therapeutic compound as well as solubilized preparations can be used.
  • the therapeutic compound is delivered at a concentration high enough to achieve a final concentration in the range of about 0.1 ⁇ mol/L to about 10 ⁇ mol/L within the target ophthalmic compartment (e.g. the posterior chamber for the treatment of retinal diseases).
  • the final concentration of the therapeutic compound is in the range of about 0.25 ⁇ mol/L to about 5 ⁇ mol/L.
  • Solid dispersions of the therapeutic compound as well as solubilized preparations can be used.
  • the precise concentration is subject to modest but not undue experimental manipulation well within the skill of the ordinary medical practitioner in order to optimize the therapeutic response.
  • Suitable vehicles include oil-in- water or water-in-oil emulsions for preparation of ointments using mineral oils, petrolatum, lanolin, glycerin and the like as well as gels such as hydrogel.
  • a preferred embodiment of the present invention involves administration of semi- solid or solid implants containing PPAR ⁇ agonists.
  • the methods of the present invention include the use of all existing synthetic and naturally occurring PPAR ⁇ agonists and those yet to be discovered.
  • Preferred PPAR ⁇ agonists useful for the application of methods described herein include the novel compounds described in the following submitted patent applications: Pershadsingh HA, Avery MA. 1,2-Dithiolane Derivatives, US Patent Application No. 09/520,208), and/or other drugs, which may be in slow release form for topical or systemic delivery. This may be accomplished in a preferred embodiment by using instrumentation and techniques described in U.S. Patent No. 5,817,075 and U.S. Patent No. 5,868,728.
  • either solid or fluid unit dosage forms can be prepared.
  • the compound of interest is mixed into formulations with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound of interest with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound of interest with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
  • Fluid unit dosage forms for oral administration such as syrups, elixirs and suspensions can be prepared.
  • the water soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholic (e.g., ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.
  • Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like. Appropriate formulations for parenteral use are apparent to the practitioner of ordinary skill.
  • the therapeutic compound is prepared in an aqueous solution (discussed below) in a concentration of from about 1 to about 100 mg/ml. More typically, the concentration is from about 10 to 60 mg/ml or about 20 mg/ml. Concentrations below 1 mg/ml may be necessary in some cases depending on the solubility and potency of the compound selected for use.
  • the formulation which is sterile, is suitable for various topical or parenteral routes including sublingual, by suppository (e.g. per-rectum or vaginal application), oral, intravascular, intradermal, by inhalation, intramuscular, intra-articular, intravenous, or other parenteral route.
  • compositions may include, depending on the formulation and mode of delivery desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which include vehicles commonly used to form pharmaceutical compositions for animal or human administration.
  • diluent is selected so as not to unduly affect the biological activity of the combination.
  • examples of such diluents which are especially useful for injectable formulations are water, the various saline, organic or inorganic salt solutions, Ringer's solution, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may include additives such as other carriers; adjuvants; or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • excipients can be included in the formulation.
  • examples include cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and aiitioxidants.
  • Any pharmacologically acceptable buffer may be used, e.g., tris or phosphate buffers.
  • Effective amounts of diluents, additives and excipients are those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc.
  • a composition of the invention includes a therapeutic compound which may be formulated with conventional, pharmaceutically acceptable, vehicles for topical, oral or parenteral administration.
  • Formulations may also include small amounts of adjuvants such as buffers and preservatives to maintain isotonicity, physiological and pH stability.
  • adjuvants such as buffers and preservatives to maintain isotonicity, physiological and pH stability.
  • Means of preparation, formulation and administration are known to those of skill. See generally Remington's Pharmaceutical Science 15th ed., Mack Publishing Co., Easton, Pa. (1980).
  • compositions described herein can be utilized with the compositions described herein to provide a continuous or long term source of therapeutic compound.
  • slow release systems are applicable to formulations for delivery via topical, intraocular, oral, and parenteral routes.
  • delivery intravascularly, intra-articularly, intramuscularly, intra- articularly, intradermally, or other parenteral route can be accomplished by injection, cannula or other invasive device designed to introduce precisely metered amounts of a desired formulation to a particular compartment or tissue.
  • delivery to certain areas within the eye, in situ can be accomplished by injection, cannula or other invasive device designed to introduce precisely metered amounts directly or contained in a reservoir for slow release in situ, of a desired formulation to a particular compartment or tissue within the eye (e.g. anterior or posterior chamber, uvea or retina).
  • a solid or semisolid implant can be delivered subretinally using the instrumentation and methods described in U.S. Patent
  • therapeutic agents of the present invention are delivered or administered topically for treating disorders involving the eye that are listed in Tables I through X. Oral administration is preferred for disorders in Tables I through X that cannot be treated effectively by topical therapy. Additionally, the agents can be delivered parenterally, especially for treatment of retinitis and degenerative retinal diseases, and for other conditions in Tables I through X, that do not respond to oral or topical therapy, or for conditions where oral or topical therapy is not feasible.
  • Parenteral therapy is typically oral, intraocular, transcutaneous, intradermal, intrathecal, intramuscular, intra-articular, by inhalation, intravascular, sublingual, by suppository (e.g. per-rectum or vaginal application), by inhalation, or other parenteral route.
  • a preferred way to practice the invention for dermatological or ophthalmic disorders in Tables I through XI to which this method is applicable, is to apply the compound of interest, in a cream, lotion, ointment, or oil based carrier, directly to the lesion.
  • concentration of therapeutic compound in a cream, lotion, or oil is 0.1 to 2.5%.
  • the preferred route of administration is oral, topical, intraocular or parenteral.
  • Topical administration is preferred in treatment of lesions of the skin as in psoriasis, external eye as in conjunctivitis, keratitis, scleritis, squamous cell carcinoma, corneal erosion, dry eye syndrome, and anterior compartment of the eye as in glaucoma, uveitis and other diseases of the uveal tract, where such direct application is practical and clinically indicated.
  • Oral administration is a preferred alternative for treatment of other lesions discussed in Tables I through XI, where direct topical application is not useful as in the treatment of chronic or acute systemic diseases, and diseases of the posterior segment of the eye, as in retinitis and other retinal degenerative diseases.
  • Intravascular (intravenous being the preferred route) administration may be necessary in disorders that cannot be effectively treated by topical or oral administration.
  • Intraocular, transcutaneous, intradermal, intrathecal, intramuscular, intra-articular injections or other invasive technique are preferred alternative in cases where the practitioner wishes to treat one or a few specific areas or lesions depending on their location within the eye.
  • the compound is delivered in an aqueous solution.
  • the therapeutic compounds are injected directly into lesions (intra-lesion administration) in appropriate cases.
  • Intradermal administration is an alternative for extraocular lesions.
  • Intra- lesional and intradermal injections are alternative routes of application for certain lesions, e.g. extraocular neoplastic or hyperplastic lesions such as squamous cell carcinoma and condyloma, respectively.
  • Inhalation therapy is preferred for pulmonary diseases, sublingual and intra-rectal suppository is preferred for rapid delivery or in clinical situations where delivery via the oral or intravascular route is inconvenient or problematic.
  • Application via vaginal topical formulation or via suppository formulation is preferred for diseases localized to the vagina or other segment of the urogenital tract.
  • the therapeutic agent may be inhaled via nebulizer, inhalation capsules, inhalation aerosol, nasal solution, intra-tracheal as a solution via syringe, or endotracheally tube as an aerosol or via as a nebulizer solution.
  • the dosage of compounds used in accordance with the invention varies depending on the compound and the condition being treated. For example, the age, weight, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy are among the factors affecting the selected dosage. Other factors include: the route of administration, the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound.
  • the dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient.
  • an effective amount of the compound is that which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • MW is the molecular weight of the compound in g/mole.
  • troglitazone is a compound encompassed by the methods of this invention.
  • an effective dose of rosiglitazone in milligrams for an average man is (10) (0.06 x 10-6 mol/L) (0.72L/kg x 70kg) (304 g/mole) or 9.2 mg.
  • the dosage per day of a thiazolidinedione of this invention will depend on the affinity of the thiazolidinedione for PPAR ⁇ .
  • the dosages of compounds with high affinity, e.g., rosiglitazone, will fall between about 0.5 mg to about 100 mg
  • of compounds of intermediate affinity will fall from about 10 mg to about 500 g
  • compounds with low affinity e.g., troglitazone
  • An oral dosing schedule is typically, a single dose once a day. However, more than one dose can be given per day. Because of the lower incidence of undesirable side effects, the compounds of this invention can be given until improvement in the inflammatory process or disease involving neovascularization is observed. Because the compounds of this invention are to some degree fat-soluble, in a preferred embodiment, the compounds are administered with food.
  • the fats in food provide a lipid micellular phase in which the PPAR ⁇ and/or PPAR ⁇ modifiers of this invention can solubilize and be more effectively absorbed.
  • a dosage range for local treatment is about 0.1% to about 10% (weight/volume) in a suitable solvent applied that permits release of the compound into the prostate tissue.
  • the dosage for local treatment will vary depending on the compound used.
  • the thiazolidinediones of this invention have different affinity for PPAR ⁇ and/or PPAR ⁇ , e.g., pioglitazone has a higher affinity for PPAR ⁇ than troglitazone.
  • the greater the affinity the more effective the compound, and the lower the dosage that is an effective amount. Therefore, a lower concentration of pioglitazone in a unit dosage form comprises an effective amount.
  • the local dosage is administered at least once a day until a therapeutic result is achieved.
  • the dosage can be administered twice a day, but more or less frequent dosing can be recommended by the clinician.
  • the compound can be tapered or discontinued. Occasionally, side effects warrant discontinuation of therapy.
  • An effective quantity of the compound of interest is employed in treatment.
  • the dosage of compounds used in accordance with the invention varies depending on the compound and the condition being treated. The age, lean body weight, total weight, body surface area, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy are among the factors affecting the selected dosage. Other factors include the route of administration the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound.
  • the dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient.
  • an oral dosing schedule is from about 0.1 mg to about 1000 mg once or twice a day depending on the binding affinity of the compound for PPAR ⁇ .
  • typical oral FDA-approved doses of the thiazolidinediones, rosiglitazone and pioglitazone for the treatment of type 2 diabetes are 4 to 8 mg, and 15 to 45 mg daily, respectively.
  • a convenient oral dose for an adult patient is 300 to 600 mg once a day.
  • a dosage range for topical treatment is about 0.5% to about 5% (weight/volume) in a gel, cream or ointment, applied twice a day.
  • a usual dose for intramuscular or intraocular injection is 1 to 10 mg, depending on the compartment of the eye to be treated and on the lean body mass of the patient.
  • a typical dosage for mtra-dermal administration is about 5 to 50 mg per injection per site.
  • a typical dosage for intravenous or intramuscular administration in an adult patient would be between 100 and 400 mg per day given in single or divided doses depending on the judgement of the practitioner.
  • the dosage is administered at least once a day until a therapeutic result is achieved.
  • the dosage is administered twice a day, but more or less frequent dosing can be recommended by the clinician.
  • the drug can be tapered or discontinued. Occasionally, side effects warrant discontinuation of therapy.
  • an effective amount of the compound is that which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • the compounds in this invention can also be given orally in combination with natural or synthetic compounds that bind to or modify the activity of the vitamin D receptor or in combination with compounds that bind to or modify the activity of the retinoid X receptor to provide for a synergistic effect in the treatment or prevention of the disorders listed in Tables I through XI.
  • examples of such compounds that provide for synergistic effect when given in combination with the drugs encompassed by the current invention include vitamin D analogs, various retinoic acid derivatives, and other ligands for retinoid X receptors or retinoic acid receptors including but not limited to compounds such as LG100268, tazarotene, TTNPB, AGN 190121, adapalene or LGD1069 (Targretin).
  • Synergistic therapeutic effects can be achieved by oral or topical administration of the drugs encompassed in the current invention together with orally, topically or intravenously administered drugs that bind to and modify the activity of either the vitamin D receptor, the glucocorticoid receptor, the intracellular enzyme calcineurin, the retinoid X receptors, or the retinoic acid receptors.
  • a preferred dosage range for administration of a retinoic acid derivative or retinoid would typically be from 0.1 to 100 mg per square-meter of body surface area, depending on the drug's ability to bind to or modify the activity of its cognate nuclear receptor, given in single or divided doses, orally or by continuous infusion, two or three times per day.
  • the preferred dosages and routes and frequency of administration of the vitamin D analogs or retinoid compounds can be similar to the dosages and routes and frequency of administration ordinarily recommended for these agents when given without PPAR ⁇ activators.
  • effective retinoids are 9-cis-retinoic acid, 13- cis-retinoic acid, all-trans-retinoic acid (at-RA).
  • Preferred retinoids for this purpose would include 13-cis-retinoic acid, tazarotene, or Targretin.
  • a preferred dosage range for systemic administration of a vitamin D analog would typically be from 0.1 to 100 mg per square-meter of body surface area, depending on the drug's ability to bind to and or activate its cognate vitamin D receptor, given in single or divided doses, orally or by continuous infusion, two or three times per day.
  • Examples of effective vitamin D analogs are 1,25-dihydroxy- vitamin D, calcipotriene and calcipotriol.
  • the dosage range and routes and frequency of administration of PPAR ⁇ activators required to achieve synergistic effects when given with vitamin D or retinoid derivatives are the same as those described elsewhere in this disclosure.
  • the preferred mode of administration of these drugs for synergistic therapeutic purposes would be orally although alternatively one can use topical or parenteral routes of administration.
  • the dosages and the modes and frequency of administration of the vitamin D or retinoid related compounds for synergistic topical therapy would be similar to those ordinarily recommended for these agents when given without PPAR ⁇ activators.
  • the dosage range and the modes and frequency required for topical administration of the flavonoid thiazolidine derivatives given in combination with vitamin D or retinoid related compounds are the same as those described elsewhere in this disclosure.
  • Synergistic therapeutic effects can be achieved by oral or topical administration of the drugs encompassed in the current invention together with orally, topically or intravenously administered natural or synthetic antioxidants.
  • vitamins such as ascorbic acid and the tocopherols (e.g. vitamin E, vitamin E succinate), carotenes and carotenoids (e.g. ⁇ -carotene), ⁇ -lipoic acid, probucols, flavones, isoflavones and flavonols (e.g. quercetin, genistein, catechin, apigenin, lutein, luteolin), glutathione and its derivatives (e.g.
  • N-acetylcysteine and dithiothreitol N-acetylcysteine and dithiothreitol
  • phytoestrogens and phenolic anthocyanidin and procyanidin derivatives (e.g. resveratrol, cyanidin, cinnamic acid).
  • the compounds of the instant invention are further useful to suppress the mediators of neurogenic inflammation (e.g. substance P or the tachykinins), and may be used in the treatment of rheumatoid arthritis; psoriasis; topical inflammation such as is associated with sunburn, eczema, or other sources of itching; and allergies, including asthma.
  • the compounds of this invention can also function as neuromodulators in the CNS, with useful applications in the treatment of Alzheimer's disease and other forms of dementia, pain (as a spinal analgesic), allodynia, and headache.
  • the compounds of the invention can provide cytoprotection.
  • Indole-based PPARgamma agonists e.g. BRL 48482 4
  • ⁇ I isoxazolinedione derivatives e.g. JTT-501 1,6,7 alpha-methoxy-beta-phenylpropanoic acids, e.g. SB 236636 1, 8,9
  • N-(2-Benzoylphenyl)-L-tyrosine derivative e.g. GI262570, GW7845 1 , 10, 11 , 12
  • Phenylacetic acid derivatives e.g. L-764486, L-764406 13,14
  • Example 1 Biological assay to screen compounds of the present invention that are activate PPAR ⁇ , PPARa or PPAR ⁇
  • Compounds of the present invention are activators of PPAR ⁇ , PPAR ⁇ or PPAR ⁇ , or any combination thereof.
  • a transient cotransfection assay can be used to screen for PPAR activity.
  • chimeras are constructed that fuse the ligand binding domains of each PPAR subtype to the DNA binding domain of the yeast transcription factor GAL4.
  • Expression plasmids for the GAL4-PPAR chimeras are then transfected into cells with a reporter construct.
  • This general assay system identifies compounds which are activators of PPAR ⁇ (full and/or partial agonists) and/or PPAR ⁇ and/or PPAR ⁇ (see, Lehmann et al, J. Biol. Chem.27Q: 12953-12956 (1995) and Murakami, K et al, Biochem. Biophys. Res. Commun. 260: 609-613 (1999) for specific protocols).
  • Example 2 Method for Screening for Compounds that Modify the Activity of PPAR ⁇ and PPARa based on Inhibition ofNF- ⁇ B activation
  • the (3 -substituted benzyl)thiazolidine-2,4-dione dithiolane derivatives bind and activate both PPAR ⁇ and PPAR ⁇ . These compounds are tested for the ability to inhibit activity of NF- ⁇ B.
  • T cell line which expresses PPAR ⁇ is stimulated with a concentration of one or a combination of: phytohemagglutinin/phorbol 12-myristate 13 -acetate (PHA/PMA), TNF- ⁇ , interferon- ⁇ or some other factor that activates NF- B.
  • PHA/PMA phytohemagglutinin/phorbol 12-myristate 13 -acetate
  • TNF- ⁇ TNF- ⁇
  • interferon- ⁇ interferon- ⁇ or some other factor that activates NF- B.
  • Activation of NF- ⁇ B is determined by electrophoretic mobility shift assay similar to that described by Rossi et al. Preincubation of the same cells with 5 ⁇ M of the test compound 2 hours prior to addition of an activator of
  • NF- ⁇ B inhibits the activation of NF-KB otherwise observed in the absence of a PPAR ligand
  • Example 4 Method for Screening for Compounds that Modify the Activity of PPAR ⁇ and PPARa based on Inhibition of NFAT activation
  • Isolated human T lymphocytes or a mammalian cell line such as a Jurkat T cell line which expresses PPAR ⁇ is stimulated with a concentration of one or a combination of PHA/PMA, TNF- ⁇ , interferon- ⁇ or some other factor that activates the nuclear factor activator of T cells (NFAT).
  • Transcriptional activation of NFAT is determined by electrophoretic mobility shift assay similar to that described by Yang et al. Preincubation of the same cells with 5 ⁇ M of the test compound for 2 hr prior to addition of an activator of NFAT inhibits the activation of NFAT otherwise observed in the absence of said compound.
  • Example 5 Method for Screening for Compounds that Modify the Activity of PPAR ⁇ and
  • Isolated human T lymphocytes or a mammalian cell line such as a Jurkat T cell line which expresses PPAR ⁇ is stimulated with a concentration of one or a combination of PHA/PMA, TNF- ⁇ , interferon- ⁇ or some other factor that activates induction of IL-2 gene expression.
  • Production of IL-2 is determined by measuring the concentration of IL-2 in the supernatant from cells using Endogen kits (Wolburn), as described by Yang et al.
  • Example 6 Methods of determining the anti-apoptotic effect of PPAR ⁇ ligands in PPARa or PPAR ⁇ -expressing cells
  • Apoptosis (cell death) is induced by adding TNF- ⁇ (Genzyme, USA) to peripheral T lymphocytes or Jurkat cells in culture.
  • the inhibitory activity of a test compound to this apoptosis is determined by using dexamethasone as the standard, a compound known to have apoptosis inhibitory activity.
  • An aliquot of RPMI-1640 culture medium (containing 10 weight % of fetal bovine serum) is added to each well of a 96-well microplate. Then, a test solution of the candidate compound in dimethylsulfoxide is added to the culture medium to give the desired final concentration (0.1 to 10 ⁇ M).
  • absorption spectrometer Microplate Reader Model 450, produced by Bio-Rad
  • Example 7 Treatment of an Intraocular Disease Selected from the following diseases: Glaucoma, Retinopathy, Optic Neuritis, Retinitis, Macular Degeneration, by Oral Administration of a PPARa/PPAR ⁇ agonist, e.g. KRP 297 or MCC 555
  • a patient having early ophthalmic manifestations of an optic neuritis e.g. optic neuritis associated with multiple sclerosis
  • a retinitis e.g. retinitis pigmentosa
  • a retinopathy e.g. hypertensive, diabetic or glaucomatous retinopathy
  • a maculopathy e.g. macular degeneration
  • the patient weighs 70 kilograms, and if female of child-bearing capacity, is given a pregnancy test to confirm that she is not pregnant.
  • KRP 297 or MCC 555 is administered orally in a dosage of about 25 mg twice daily with a fat-containing meal.
  • the patient is evaluated by an ophthalmologist experienced in the ophthalmic manifestations of retinal diseases at monthly intervals for 3 months. Regression of the disease or improvement in his clinical status is evaluated by monitoring the visual fields, color vision and visual acuity. If regression is not evident or minimal, the dose is increased to 50 mg twice daily. Additionally, a complete blood count, including wliite cell count and differential, a platelet count, and liver function tests (such as levels of alkaline phosphatase, lactate dehydrogenase, and aminotransferases) are checked prior to treatment and monthly thereafter. The dosage is tapered to maintenance, 25 mg daily.
  • Late disease A similar patient with late ophthalmic manifestations one of the diseases described, is selected for therapy. The approach is the same as for the foregoing patient, except that the starting dose is 50 mg twice daily. After 12 months, the dose may be decreased to a maintenance dose of 25 mg once or twice daily.
  • Example 8 A Clinical Trial, Synergistic (Adjunctive) Therapy for Preventing Acute and Chronic Allograft Rejection
  • Acute rejection is a significant risk factor for chronic rejection, and chronic rejection is an important cause of late graft loss.
  • Monoclonal antibodies that selectively block the interleukin-2 receptors on activated T-helper cells are used for immunoprophylaxis or anti-lymphocyte globulins for induction therapy to provide reduced dosing of cyclosporine A throughout the early post-transplantation course.
  • a PPAR ⁇ agonist is effective adjunctive therapy for preventing acute and chronic allograft rejection.
  • the PPAR ⁇ agonist is useful for providing reduced dosing of immunosuppressive therapy, including cyclosporine A, tacrolimus, azathioprine, mycophenolate or other related therapy to preventing allograft rejection throughout both early and late phases post-transplantation.
  • the PPAR ⁇ agonist is used with one or more anti-rejection drug, or in combination with a RXR agonist, or a PPAR ⁇ /RXR agonist, and/or a vitamin D receptor agonist, and/or a glucocorticoid receptor agonist, and/or an estrogen receptor agonist, and/or an androgen receptor agonist.
  • the treatment can be modified to include combination therapy with a thiazolidinedione (PPAR ⁇ ligand) or rexinoid (e.g. LG100754, a PPAR ⁇ /RXR heterodimer ligand) and another immunosuppressive compound traditionally used for preventing allograft rejection.
  • PPAR ⁇ ligand thiazolidinedione
  • rexinoid e.g. LG100754, a PPAR ⁇ /RXR heterodimer ligand
  • another immunosuppressive compound traditionally used for preventing allograft rejection.
  • examples of such compounds that provide for synergistic effect when given in combination with the drugs encompassed by the current invention include ligands for the glucocorticoid nuclear receptor ligand (e.g. prednisone), inhibitors of purine synthesis (e.g.
  • azathioprine and mycophenolate inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes (e.g. cyclosporine, tacrolimus, sirolimus).
  • activated lymphocytes e.g. cyclosporine, tacrolimus, sirolimus.
  • One or a combination of these compounds are employed (at dosages described above in Dosase and Schedules) in clinical trials at doses sufficient to prevent or treat allograft rejection.
  • the PPAR ⁇ /PPAR ⁇ dual agonist is selected from the group consisting of: KRP 297, MCC 555, JTT-501, AZ 242, NNC 61-0029 (DRF-2725) up to 50 mg daily (15 to 30 mg preferred).
  • the PPAR ligand may also be a PPAR ⁇ partial agonist, and is administered alone or with another agent to provide a synergistic clinical effect.
  • Examples are: a.. A PPAR ⁇ /PPAR ⁇ agonist is administered in combination with prednisone at an FDA- approved dose. b. A PPAR ⁇ /PPAR ⁇ agonist is administered in combination with prednisone and cyclosporine A or tacrolimus at an FDA-approved dose, or sirolimus at a dose used in clinical trials. c. A PPAR ⁇ /PPAR ⁇ agonist is administered in combination with prednisone and cyclosporine A or tacrolimus or sirolimus, and azathioprine or mycophenolate. d.
  • a PPAR ⁇ partial agonist such as GW0072 is administered in combination with one or more FDA-approved immunosuppressive transplant rejection therapeutic compound, as described in examples a, b and c above.
  • FDA-approved immunosuppressive transplant rejection therapeutic compound as described in examples a, b and c above.
  • a rexinoid PPAR ⁇ /RXR heterodimer ligand e.g. LG100754 is administered in combination with one or more FDA-approved immunosuppressive transplant rejection therapeutic compound at approved dosages as described in examples a, b and c above.
  • PPAR ⁇ /PPAR ⁇ dual agonists selected from the group consisting of: KRP 297, MCC 555, JTT-501, AZ 242, NNC 61-0029 (DRF-2725) up to 50 mg daily (15 to 30 mg preferred), may also be employed in an analogous fashion.
  • the patient presents acutely with the neurological manifestations of multiple sclerosis, and the diagnosis is confirmed by clinical laboratory and pathological diagnostic tests.
  • the patient is evaluated by a neurologist experienced in the clinical and laboratory manifestations of multiple sclerosis lesions.
  • the patient weighs 70 kilograms, and if female of child-bearing capacity, is given a pregnancy test to confirm that she is not pregnant.
  • a compound known to activate PPAR ⁇ namely, the thiazolidinedione, pioglitazone is administered orally in a dosage of 15 milligrams daily during the acute episode, and is titrated up to 30 mg daily then 45 mg daily at weekly intervals.
  • Regression of the disease or improvement in his clinical status is evaluated by monitoring improvement in motor deficits.
  • Reduction of the systemic inflammation associated with the disease is assessed by performing bi-monthly measurements of high sensitivity-C-reactive protein (hs-CRP).
  • hs-CRP high sensitivity-C-reactive protein
  • a reduction in the hs-CRP by 50% within 3 months of initiating therapy is considered to be a positive response to the therapy.
  • a complete blood count, white cell count and differential, a platelet count, liver function tests (such as levels of alkaline phosphatase, lactate dehydrogenase, and aminotransferases), erythrocyte sedimentation rate and plasma interleukin-2 levels are checked prior to treatment and monthly thereafter. After 6 months treatment, the dosage is tapered to a maintenance dose of 30 mg.
  • Late disease A similar patient with chronic recalcitrant multiple sclerosis, having failed existing approved therapies such as interferon injections, and with late manifestations of the disease, such as weight loss, cachexia, rigidity, vision loss, or quadriplegia, is selected for therapy.
  • the approach is the same as for the foregoing patient, except that the starting dose of 30 mg pioglitazone once daily for 3 months, and is increased to 45 mg thereafter.
  • Regression of the disease or improvement in his clinical status is evaluated by monitoring improvement in motor deficits.
  • a reduction in the hs-CRP by 50% within 3 months of initiating therapy is considered to be a positive response to the therapy.
  • Example 10 Treatment of a PPAR-Mediated Inflammatory, Proliferative or Degenerative Disease with a PPAR ⁇ /PPARa Dual Agonist or a PPAR ⁇ /PPAR ⁇ Dual Agonist.
  • the PPAR-mediated disease is selected from one of the following: a degenerative neurological disease (e.g. Alzheimer's disease), rheumatoid arthritis, atherosclerosis, depression, post-myocardial cardiomyopathy, congestive heart failure, hepatic fibrosis, a pulmonary disease (asthma or chronic obstructive pulmonary disease), a carcinogenic disease, or other inflammatory, proliferative, or degenerative disease (Horrocks LA, Yeo YK. Pharmacol Res 1999; 40:211-25; Youdim KA, Int J Dev Neurosci. 2000; 18:383-99; Martinez M, et al. Rev Neurol 1999; 28 Suppl S59-64).
  • the PPAR ⁇ /PPAR ⁇ dual agonist is selected from the group consisting of: MCC 555,
  • the PPAR ⁇ /PPAR ⁇ dual agonist is selected from the group consisting of:GW9578, KRP 297, with a dose of up to 50 mg daily (15 to 30 mg preferred).
  • the patient presents acutely or chronically ill and the diagnosis is confirmed by clinical laboratory and pathological diagnostic tests.
  • the patient is evaluated by a specialist experienced in the clinical and laboratory manifestations of the index disease.
  • the patient weighs 70 kilograms, and if female of child-bearing capacity, is given a pregnancy test to confirm that she is not pregnant.
  • one of the compounds identified above is administered orally in a dosage of 10 mg daily, and is titrated up to 30 mg daily at weekly intervals.
  • Regression of the disease or improvement in his clinical status is evaluated by monitoring standard clinical indicators. Additionally, a complete blood count, white cell count and differential, a platelet count, liver function tests (such as levels of alkaline phosphatase, lactate dehydrogenase, and aminotransferases), erythrocyte sedimentation rate and plasma high sensitivity-C-reactive protein are checked prior to treatment and monthly thereafter. After 3 to 6 months treatment, the dosage is tapered to a maintenance dose of 10 or 20 mg daily. The patients response to therapy is monitored by laboratory markers of the respective disease, and inflammatory markers of systemic inflammation to monitor amelioration of the inflammatory response to assess clinical improvement.
  • Example 11 Combination Treatment of a PPAR-Mediated Inflammatory, Proliferative or Degenerative Disease with PPAR ⁇ Agonist or a Mixed PPAR ⁇ /PPARa Agonist (Co-Ligand) and an Estrogen Receptor Ligand - A Clinical Trial
  • the PPAR-mediated disease is selected from one of the following: a degenerative neurological (Alzheimer's disease) or uveo-retinal disease, arthritis, atherosclerosis, depression, cardiomyopathy, congestive heart failure, post-myocardial fibrosis, hepatic fibrosis, pulmonary disease (asthma, COPD), a carcinogenic disease, or other inflammatory, proliferative, or degenerative disease (Horrocks LA, Yeo YK. Pharmacol Res. 1999; 40:211-25; Youdim KA, Int J Dev Neurosci. 2000; 18:383-99; Martinez M, et al. Rev Neurol 1999; 28 Suppl l :S59-64).
  • a degenerative neurological Alzheimer's disease
  • uveo-retinal disease arthritis
  • atherosclerosis depression
  • cardiomyopathy congestive heart failure
  • post-myocardial fibrosis hepatic fibrosis
  • the PPAR ⁇ agonist or mixed PPAR ⁇ /PPAR ⁇ agonist or co-ligand are 4-substituted or 3-substituted benzodithiolanyl derivatives (e.g. KRP 297), respectively described in this invention, administered at doses of 1 to 2 mg twice daily oral dose.
  • examples of other mixed PPAR ⁇ /PPAR ⁇ co-ligands are KRP 297 (50 to 500 mg, daily oral dose.
  • the estrogen receptor (ER) ligand is selected from: estradiol (0.5 to 10 mg, daily oral dose, 1.25 mg preferred), tamoxifen or 4-OH-tamoxifen (5 to 50 mg, daily oral dose, 15 mg preferred), clomifene, coumestrol, genistein (10 to 200 mg, daily oral dose, 50 mg preferred), or biochanin A, a genistein precursor (5 to 100 mg, daily oral dose, 20 mg preferred).
  • estradiol 0.5 to 10 mg, daily oral dose, 1.25 mg preferred
  • tamoxifen or 4-OH-tamoxifen 5 to 50 mg, daily oral dose, 15 mg preferred
  • clomifene 5-fluorouracil
  • coumestrol genistein
  • genistein 10 to 200 mg, daily oral dose, 50 mg preferred
  • biochanin A a genistein precursor
  • These pharmacological compositions may be used to treat acute or chronic disease or may be used prophylactically to prevent the onset of the disease.
  • the patient presents acutely or chronically with the manifestations of Alzheimer's disease (a neuro-degenerative disease), glaucomatous retinopathy (a neuro-retinal degenerative disease), atherosclerosis (an inflammatory ischemic vascular disease), ulcerative colitis (an inflammatory bowel disease), hepatic fibrosis (a degenerative liver disease), or a carcinogenic disease of the breast or prostate.
  • Alzheimer's disease a neuro-degenerative disease
  • glaucomatous retinopathy a neuro-retinal degenerative disease
  • atherosclerosis an inflammatory ischemic vascular disease
  • ulcerative colitis an inflammatory bowel disease
  • hepatic fibrosis a degenerative liver disease
  • carcinogenic disease of the breast or prostate.
  • the diagnosis is confirmed by clinical laboratory and pathological diagnostic tests.
  • the patient is evaluated by a specialist experienced in the clinical and laboratory manifestations of the index disease.
  • the patient weighs 70 kilograms, and if female of child-bearing capacity, is given
  • KRP 297 is administered orally in a dosage of 100 mg twice daily. Regression of the disease or improvement in his clinical status is evaluated by monitoring standard clinical indicators. Additionally, a complete blood count, white cell count and differential, a platelet count, liver function tests (such as levels of alkaline phosphatase, lactate dehydrogenase, and ammotransferases), erythrocyte sedimentation rate and plasma high sensitivity-C-reactive protein are checked prior to treatment and monthly thereafter. The patients response to therapy is additionally monitored by laboratory markers of the respective disease, and inflammatory markers of systemic inflammation to monitor amelioration of the inflammatory response to determine clinical improvement.
  • Example 12 Combination Treatment of a PPAR-Mediated Inflammatory, Proliferative Dermatological (Skin) Disease with PPAR ⁇ Agonist or a Mixed PPAR ⁇ /PPARa Agonist (Co- Ligand) and a Vitamin D Receptor Ligand - A Clinical Trial
  • the PPAR-mediated disease is an inflammatory, proliferative or degenerative skin disease such as psoriasis, keratitis, hidradenitis, ichthyosis, acne, rosacea, verrucae and other HPV infections, atopic dermatitis, allergic dermatitis, chemical (irritant) dermatitis, seborrheic dermatitis, solar dermatitis, acute and chronic eczema, seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis, skin aging, thinning skin, dry skin, wrinkle formation, photo-induced skin aging, keloids, lichen planus.
  • the PPAR ⁇ agonist or mixed PPAR ⁇ /PPAR ⁇ agonist or co-ligand are 4-substituted or
  • 3-substituted benzodithiolanyl derivatives are administered at doses consistent with the EC50 for PPAR ⁇ and/or PPAR, and with the pharmacokinetic area under the curve (AUC), and is given as a once or twice daily oral dose, or in a pharmaceutical composition for topical administration, with active ingredient at a concentration ranging from 0.01 to 2.0%, 0.25% preferred.
  • PPAR ⁇ -specific agonists are selected from the group consisting of: a thiazolidinedione given orally, e.g. rosiglitazone, 4 mg twice daily or pioglitazone, 45 mg once daily).
  • Examples of mixed PPAR ⁇ /PPAR ⁇ co- ligands are KRP 297 (25 to 250 mg, daily oral dose).
  • the vitamin D receptor (VDR) ligand is a natural or synthetic vitamin D derivative.
  • An orally administered vitamin D derivative is selected from: dihydrotachysterol (1 mg daily), 1,25-dihydroxycholecalciferol (1 meg daily), 25-hydroxycholecalciferol (0.1 mg daily), ergocholecalciferol (1.25 mg daily), and cholecalciferol (1 mg daily).
  • Synthetic vitamin D derivatives are administered topically and is selected from the group consisting of calcipotriene and calcitriol (both at a concentration of 0.005%) in an ointment or lotion or shampoo). These pharmacological compositions may be used to treat acute or chronic disease or may be used prophylactically to prevent the onset of the disease.
  • Example 13 Use of Pioglitazone as Synergistic (Adjunctive) Therapy in the Treatment of Multiple Sclerosis (MS) - A Clinical Trial
  • a PPAR ⁇ and/or PPAR ⁇ agonist may be used adjunctively in combination therapy with any of the existing (approved) therapies (identified above) for treating MS.
  • existing therapies identified above
  • rosiglitazone, pioglitazone, KRP 297, MCC 555 or JTT-501 for the stated adjunctive use at doses outlined above.
  • the patient presents acutely with the neurological manifestations of multiple sclerosis, and the diagnosis is confirmed by clinical laboratory and pathological diagnostic tests.
  • the patient is evaluated by a neurologist experienced in the clinical and laboratory manifestations of multiple sclerosis lesions.
  • the patient is a male weighing 70 kilograms or a female weighing 50 kilograms and being treated with an interferon ⁇ preparation, Copaxone, or Novantrone.
  • An adjunctive PPAR ⁇ agonist, a PPAR ⁇ agonist, or a PPAR ⁇ and PPAR ⁇ co-agonist (co-activator) is selected from one of the following group of compounds: 1) PPARv/PPARa lisand:
  • KRP 297 7.5 mg to 50 mg QD or as split dose BID.
  • Bezafibrate 25 mg to 200 mg QD or as split dose BID.
  • Preferred dose 50 to 100 mg QD MCC 555 5 mg to 30 mg QD or as split dose BID.
  • JTT-501 5 mg to 30 mg QD or as split dose BID.
  • Adjunctive therapy is initiated at one-half the preferred dose as indicated above.
  • the dose is doubled within 6 to 8 wks of initiation of said adjunctive therapy.
  • the patient is monitored for improvement based on laboratory and clinical findings.
  • the regime is continued as medically indicated to one of skill in the art of treating MS.
  • Tables I through X in the attached appendix which are incorporated in whole by this reference, provide further examples of diseases or disorders treatable with methods described in this invention.

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Abstract

L'invention concerne des procédés d'utilisation de ligands PPAR dans le traitement de maladies inflammatoires endocrines, dermatologiques, cardio-vasculaires, immunologiques, neurologiques, ophtalmiques, néoplasiques, pulmonaires, et de dysfonctionnements liés à l'âge. L'invention concerne de plus des méthodes de traitement de ces états et maladies, qui comprennent l'étape consistant à administrer à un être humain ou à un animal nécessitant un tel traitement une quantité thérapeutique de compositions pharmacologiques contenant un excipient pharmaceutiquement acceptable et un agoniste de PPARη qui active par réaction croisée PPARα et/ou PPARδ, ou un agoniste partiel de PPARη, ou un agoniste de PPARη/RXR permettant d'inverser, de ralentir, d'arrêter ou de prévenir le processus inflammatoire ou dégénératif.
PCT/US2001/025668 2000-08-17 2001-08-16 Traitements de maladies inflammatoires WO2002013812A1 (fr)

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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018010A1 (fr) * 2001-08-23 2003-03-06 Mitsubishi Pharma Corporation Agent prophylactique et/ou curatif pour les maladies induites par l'activite de l'arteriosclerose
WO2003045383A1 (fr) * 2001-11-26 2003-06-05 Arachnova Therapeutics Ltd. Utilisation d'activateurs des ppar dans le traitement de fibrose pulmonaire
WO2003096997A1 (fr) * 2002-05-14 2003-11-27 The Gillette Company Limitation de la pousse des poils
WO2004026406A1 (fr) * 2002-09-20 2004-04-01 Alcon, Inc. Utilisation d'inhibiteurs de la synthese des cytokines dans le traitement des troubles associes a la keratoconjonctivite seche
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EP1497420A4 (fr) * 2002-04-30 2005-04-27 Alcon Inc Agents regulant, inhibant ou modulant l'activite et/ou l'expression du facteur de croissance du tissu conjonctif (ctgf) utilises comme moyen unique pour reduire la pression intraoculaire et traiter les retinopathies glaucomateuses/neuropathies optiques
WO2005108396A1 (fr) * 2004-05-11 2005-11-17 Santen Pharmaceutical Co., Ltd. Agent thérapeutique pour une affection de kératoconjonctivite
JP2005350451A (ja) * 2004-05-11 2005-12-22 Santen Pharmaceut Co Ltd 角結膜障害治療剤
WO2005097098A3 (fr) * 2004-04-01 2005-12-22 Aventis Pharma Inc Utilisation d'agonistes delta de recepteur active de la proliferation des peroxysomes destines au traitement de la sep et d'autres troubles de demyelinisation
WO2006010504A1 (fr) * 2004-07-29 2006-02-02 Werner Bollag Traitement de la sclerose en plaques au moyen d'antagonistes de rxr
US7223761B2 (en) 2003-10-03 2007-05-29 Amgen Inc. Salts and polymorphs of a potent antidiabetic compound
EP1637161A4 (fr) * 2003-04-22 2007-06-27 Astellas Pharma Inc REMEDE CONTRE DES MALADIES CEREBRALES NEURODEGENERATIVES UTILISANT UN AGONISTE DES PPAR [delta]
EP1461028A4 (fr) * 2001-12-07 2007-07-25 Univ California Traitement de la degenerescence maculaire liee au vieillissement
FR2897534A1 (fr) * 2006-02-17 2007-08-24 Galderma Res & Dev Utilisation du tesaglitazar pour la preparation d'une composition pharmaceutique destinee au traitement des affections dermatologiques
US7323481B2 (en) * 2001-04-06 2008-01-29 Hoffmann-La Roche Inc. Thiazolidinediones alone or in combination with other therapeutic agents for inhibiting or reducing tumour growth
US7470659B2 (en) 2001-12-07 2008-12-30 The Regents Of The University Of California Methods to increase reverse cholesterol transport in the retinal pigment epithelium (RPE) and Bruch's membrane (BM)
US7601841B2 (en) 2000-06-28 2009-10-13 Amgen Inc. Quinolinyl and benzothiazolyl modulators
US7626033B2 (en) 1999-06-30 2009-12-01 Amgen Inc. Compounds for the modulation of PPARγ activity
WO2010015818A1 (fr) * 2008-08-07 2010-02-11 Argenta Discovery Limited Traitement de maladie respiratoire
WO2010150014A1 (fr) 2009-06-24 2010-12-29 Pulmagen Therapeutics (Inflammation) Limited Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
US20110028527A1 (en) * 2009-07-30 2011-02-03 Aestus Therapeutics, Inc. Methods of Treating Neuropathic Pain with Benzimidazole Derivative Agonists of PPARgamma
WO2011015868A1 (fr) 2009-08-05 2011-02-10 Pulmagen Therapeutics (Inflammation) Limited Procédé de résolution énantiomérique
WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
RU2449789C2 (ru) * 2007-05-21 2012-05-10 Сэндзю Фармасьютикал Ко., Лтд. Лекарственное средство, содержащее prarδ агонист
US8236786B2 (en) 2008-08-07 2012-08-07 Pulmagen Therapeutics (Inflammation) Limited Respiratory disease treatment
US8362064B2 (en) 2008-12-30 2013-01-29 Pulmagen Theraputics (Inflammation) Limited Sulfonamide compounds for the treatment of respiratory disorders
EP2515830A4 (fr) * 2009-12-21 2014-06-04 B C Unlimited Liability Company Compositions et méthodes pour l'augmentation de la graisse cellulaire et le blanchiment de la peau
US8946256B2 (en) 2009-12-21 2015-02-03 Biocosmeceuticals, LLC Compositions and methods for treatment of vitiligo
WO2019193348A1 (fr) * 2018-04-04 2019-10-10 Wren Therapeutics Limited Thérapie pour affections ophtalmologiques
WO2019240946A1 (fr) 2018-06-11 2019-12-19 The Regents Of The University Of California Déméthylation pour traiter une maladie oculaire
WO2019193347A3 (fr) * 2018-04-04 2020-01-09 Wren Therapeutics Limited Thérapie pour une maladie de mauvais repliement de protéines
WO2024040256A3 (fr) * 2022-08-19 2024-04-25 National Health Research Institutes Combinaisons pharmaceutiques et méthodes de prévention ou de traitement de maladies neurodégénératives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981586A (en) * 1997-05-23 1999-11-09 Pershadsingh; Harrihar A. Methods for treating proliferative and inflammatory skin diseases
US6034110A (en) * 1998-01-12 2000-03-07 Allergan Sales, Inc. Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid and a PPARγ ligand

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981586A (en) * 1997-05-23 1999-11-09 Pershadsingh; Harrihar A. Methods for treating proliferative and inflammatory skin diseases
US6034110A (en) * 1998-01-12 2000-03-07 Allergan Sales, Inc. Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid and a PPARγ ligand

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7626033B2 (en) 1999-06-30 2009-12-01 Amgen Inc. Compounds for the modulation of PPARγ activity
US7601841B2 (en) 2000-06-28 2009-10-13 Amgen Inc. Quinolinyl and benzothiazolyl modulators
US7323481B2 (en) * 2001-04-06 2008-01-29 Hoffmann-La Roche Inc. Thiazolidinediones alone or in combination with other therapeutic agents for inhibiting or reducing tumour growth
WO2003018010A1 (fr) * 2001-08-23 2003-03-06 Mitsubishi Pharma Corporation Agent prophylactique et/ou curatif pour les maladies induites par l'activite de l'arteriosclerose
WO2003045383A1 (fr) * 2001-11-26 2003-06-05 Arachnova Therapeutics Ltd. Utilisation d'activateurs des ppar dans le traitement de fibrose pulmonaire
US7470659B2 (en) 2001-12-07 2008-12-30 The Regents Of The University Of California Methods to increase reverse cholesterol transport in the retinal pigment epithelium (RPE) and Bruch's membrane (BM)
EP1461028A4 (fr) * 2001-12-07 2007-07-25 Univ California Traitement de la degenerescence maculaire liee au vieillissement
US7470660B2 (en) 2001-12-07 2008-12-30 The Regents Of The University Of California Treatment for dark adaptation
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AU2003221762B2 (en) * 2002-04-30 2008-09-25 Alcon, Inc. Agents which regulate, inhibit or modulate the activity and/or expression of connective tissue growth factor (CTGF) as a unique means to both lower intraocular pressure and treat glaucomatous retinopathies/optic neuropathies
US7351407B2 (en) 2002-04-30 2008-04-01 Alcon, Inc. Agents which regulate, inhibit, or modulate the activity and/or expression of connective tissue growth factor (CTGF) as a unique means to both lower intraocular pressure and treat glaucomatous retinopathies/optic neuropathies
EP1497420A4 (fr) * 2002-04-30 2005-04-27 Alcon Inc Agents regulant, inhibant ou modulant l'activite et/ou l'expression du facteur de croissance du tissu conjonctif (ctgf) utilises comme moyen unique pour reduire la pression intraoculaire et traiter les retinopathies glaucomateuses/neuropathies optiques
JP2006131643A (ja) * 2002-04-30 2006-05-25 Alcon Inc 眼内圧の低下および緑内障性網膜症／眼神経障害の処置の両方のための独特の手段としての、結合組織増殖因子（ｃｔｇｆ）の活性および／または発現を調節するか、阻害するか、または調整する薬剤
WO2003096997A1 (fr) * 2002-05-14 2003-11-27 The Gillette Company Limitation de la pousse des poils
US7026296B2 (en) 2002-09-20 2006-04-11 Alcon, Inc. Methods of treating dry eye disorders
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WO2011098746A1 (fr) 2010-02-09 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
WO2011098799A2 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
WO2011098801A1 (fr) 2010-02-10 2011-08-18 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladies inflammatoires
WO2019193348A1 (fr) * 2018-04-04 2019-10-10 Wren Therapeutics Limited Thérapie pour affections ophtalmologiques
WO2019193347A3 (fr) * 2018-04-04 2020-01-09 Wren Therapeutics Limited Thérapie pour une maladie de mauvais repliement de protéines
WO2019240946A1 (fr) 2018-06-11 2019-12-19 The Regents Of The University Of California Déméthylation pour traiter une maladie oculaire
WO2024040256A3 (fr) * 2022-08-19 2024-04-25 National Health Research Institutes Combinaisons pharmaceutiques et méthodes de prévention ou de traitement de maladies neurodégénératives

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