WO1998043081A1 - Traitement de troubles gastro-intestinaux au moyen de modulateurs du recepteur active de la proliferation des peroxysomes (ppar) - Google Patents

Traitement de troubles gastro-intestinaux au moyen de modulateurs du recepteur active de la proliferation des peroxysomes (ppar) Download PDF

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WO1998043081A1
WO1998043081A1 PCT/US1998/005852 US9805852W WO9843081A1 WO 1998043081 A1 WO1998043081 A1 WO 1998043081A1 US 9805852 W US9805852 W US 9805852W WO 9843081 A1 WO9843081 A1 WO 9843081A1
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Prior art keywords
ppar
disease
gastrointestinal
gene
expression
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PCT/US1998/005852
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English (en)
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Anne-Marie Lefebvre
Johan Auwerx
Michael R. Briggs
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Ligand Pharmaceuticals Incorporated
Institut Pasteur
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Priority to AU67735/98A priority Critical patent/AU6773598A/en
Publication of WO1998043081A1 publication Critical patent/WO1998043081A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases

Definitions

  • This invention relates to methods and pharmaceutical compounds for treating gastrointestinal diseases.
  • the invention also relates to screening methods for identifying useful pharmaceutical compounds for treating gastrointestinal diseases.
  • PPARs Peroxisome proliferator activated receptors
  • ⁇ Three distinct PPARs, termed ⁇ , ⁇ (also called ⁇ , NUC-1 or FAAR) and ⁇ , each encoded by a separate gene and showing a distinct tissue distribution pattern, have been described [Reviews: Desvergne, B. and Wahli , W., Birkhauser. 1: 142-176 (1994); Green, S., Mutation Res. 333: 101-109 (1995); Schoonjans, K. et al,
  • PPARs heterodimerize with retinoid X receptors (RXRs), another subfamily of nuclear hormone receptors, and alter the transcription of target genes after binding to PPAR response elements (PPREs).
  • RXRs retinoid X receptors
  • PPREs PPAR response elements
  • a PPRE typically contains a direct repeat of the nuclear receptor hexameric DNA core recognition motif, an arrangement termed DR-1 when recognition motifs are spaced by 1 nucleotide [Schoonjans, K. et al, J. Lipid
  • PPAR ⁇ farnesoid PPAR ⁇
  • ⁇ prostaglandin J derivatives and thiazolidinediones
  • Numerous PPAR target genes have been identified so far [Review: Schoonjans, K. et al, Biochim. Biophys. Acta. 1302: 93-109 (1996)]
  • additional target genes continue to be identified [Hertz, R. et al, Biochem. J. 319: 241-248 (1996); Ren, B. et al, J. Biol. Chem. 271: 17167-17173 (1996)]. Since they are activated by various fatty acid metabolites as well as several drugs used in the treatment of metabolic disorders, PPARs can be considered as key messengers responsible for the translation of nutritional, pharmacological and metabolic stimuli into changes in gene expression.
  • PPAR ⁇ was the first PPAR to be identified [Isseman, I. and Green, S., Nature 347:
  • PPAR ⁇ is most effectively stimulated by peroxisome proliferators and mediates the response to peroxisome proliferators in rodents [Lee, S. S. T. et al, Mol Cell. Biol. 15: 3012-3022 (1995)]. Recently, it was shown that peroxisome proliferators of the fibrate group are not only activators of PPAR ⁇ , but are also authentic ligands for this receptor [Devchand, P. R. et al, Nature 384: 39-43 (1996)]. PPAR ⁇ is expressed mainly in tissues that have a high level of fatty acid catabolism such as the liver [Braissant, O. et al, Endocrinology 137: 354-366 (1995)]. In the liver, PPAR ⁇ is responsible for the oxidation of fatty acids and the detoxification of several xenobiotic compounds.
  • PPAR ⁇ PPAR ⁇
  • they have now also been shown to be direct ligands of this PPAR subtype [Devchand, P. R. et al, Nature 384: 39-43 (1996)]. It has also been shown that PPAR ⁇ expression can be induced by transcriptional mechanisms upon treatment with anti-inflammatory glucocorticoids [Lemberger, T. et al,
  • PPAR ⁇ was the first PPAR for which ligands were identified. In rodents, PPAR ⁇ was thought to be confined to adipose tissue. However, low levels of PPAR ⁇ expression were detected in other tissues. This led to the suggestion that PPAR ⁇ is a key factor triggering adipocyte differentiation, a hypothesis later confirmed [Spiegelman, B. M. and
  • PPAR ⁇ 1 has been shown to be the most common form in humans [Mukherjee, R. et al, J. Biol. Chem. 272: 8071-8076 (1997)].
  • PPREs have been identified in several genes that play crucial roles in adipocyte differentiation, most of them affecting lipid storage and control of metabolism. Examples are fatty acid binding protein (aP2) [Tontonoz, P. et al, Genes Dev. 8: 1224-1234 (1994)], phosphoenolpyruvate carboxykinase (PEPCK) [Tontonoz, P. et al, Mol Cell. Biol. 15: 351-357 (1995)], Acyl CoA Synthase (ACS) [Schoonjans, K. et al, Eur. J. Biochem. 216: 615-622 (1993); Schoonjans, K. et al, J. Biol. Chem.
  • aP2 fatty acid binding protein
  • PEPCK phosphoenolpyruvate carboxykinase
  • ACS Acyl CoA Synthase
  • prostaglandin J2 was shown to be a naturally occurring ligand [Forman, B. M. et al, Cell 83: 803-812 (1995); Kliewer, S. A. et al, Cell 83: 813-819 (1995)] and the anti-diabetic thiazolidinediones (TZDs) [Forman, B. M. et al, Cell 83: 803-812 (1995); Lehmann, J. M. et al, J. Biol. Chem. 270: 12953-12956 (1995)] were shown to be synthetic ligands for PPAR ⁇ .
  • TZDs are currently being developed as insulin sensitizers for the treatment of non-insulin dependent diabetes mellitus (NIDDM) [Reviews: Hulin, B. et al, Current Pharm. Design 2: 85-102 (1996); Saltiel, A. R. and Olefsky, J. M., Diabetes 45: 1661-1669 (1996)].
  • NIDDM non-insulin dependent diabetes mellitus
  • their relative potency to activate PPAR ⁇ in vitro correlates well with their anti-diabetic potency in vivo, suggesting that PPAR ⁇ mediates their antj-diabetic effect [Berger, J.
  • Gastrointestinal disorders are very frequent in Western populations. The most prevalent of these disorders are: peptic ulcer disease, inflammatory bowel disease such as Crohn's disease and colitis ulcerosa, and intestinal neoplasias, such as gastric and colon cancer.
  • Peptic ulcer disease is used to refer to a group of ulcerative disorders of the upper GI tract that appear to have acid-pepsin formation in common in their pathogenesis.
  • the major forms of peptic ulcer are duodenal and gastric ulcer and the Zollinger-Ellison syndrome.
  • the presence or absence of peptic ulcer is determined by the delicate interplay between gastric acid secretion and mucosal resistance.
  • Peptic ulcer disease is present when the aggressive effects of acid-pepsin dominate over the protective effects of gastric or duodenal mucosa. Recently it was shown that colonization with Helicobacter pylori is one of the factors that predisposes the development of peptic ulcer disease.
  • IBD Inflammatory bowel disease
  • IBD IBD remain unknown, it is certain that genetic, infectious, immunologic and environmental factors contribute to the disease. IBD is more common in Western populations, and the frequency of its diagnosis has been increasing. In Europe the disease shows a North-South gradient with its highest incidence in the North. Colitis ulcerosa and
  • Crohn's disease have an estimated prevalence of 115/100,000 and 30/100,000, respectively.
  • the complaints and physical findings are specific and consist of abdominal pain and distress, fever, malaise, malabsorption, weight loss, and (bloody) diarrhea.
  • IBD is a severe disorder that shows a chronic and intermittent course and is still associated with a significant mortality (approximately 5%).
  • the medical treatment consists of sulfasalazine and antibiotics (metronidazole, ciproflaxin) and is sometimes accompanied by immunosuppressive therapy (corticosteroids or drugs as azathioprine, methotrexate or cyclosporin).
  • Surgical treatment is usually reserved for disease resistant to medical approach or for complications of IBD, such as intestinal obstruction or perforation.
  • Cancers of the gastrointestinal tract are also frequently diagnosed. Gastric cancer is frequently seen in Japan and in parts of South America and Eastern Europe, whereas it is less frequent in the United States. Colon cancer, on the other hand, is frequent in the United States where it accounts for 20 % of all cancer related deaths. Symptoms of these cancers are nonspecific. Anorexia, weight loss, blood in the stool, change in bowel habits, and fatigue are often-heard complaints. Diagnosis relies on radiological and endoscopic examination and anatomopathological analysis of a biopsy specimen, and is complemented by a careful staging, evaluating the presence of potential metastasis. Curative therapy consists of surgical resection of the affected part of the GI tract.
  • Chemo- and radiotherapy can be combined with surgical intervention especially in the case of metastatic cancers.
  • the 5-year survival rate for a curative surgical intervention is 50 % for both colon and gastric cancer. Nevertheless prognosis for gastric cancer is worse because it is often diagnosed at a later stage and has a more aggressive nature.
  • Proliferator Activated Receptors are present in the human gastrointestinal (GI) tract and a variety of GI diseases may be treated with modulators of PPARs, particularly modulators of PPAR ⁇ .
  • the present invention relates to methods and compositions for treating a host having a gastrointestinal (GI) disease by administering to the host a composition containing a pharmaceutically effective amount of a modulator of a Peroxisome Proliferator Activated Receptor (PPAR), particularly a modulator of PPAR ⁇ .
  • GI gastrointestinal
  • PPAR Peroxisome Proliferator Activated Receptor
  • the host may be a human patient or an animal model of human GI disease.
  • the compositions of this invention are adapted to cure, improve or prevent one or more symptoms of GI disease in the host.
  • a preferred composition is highly potent and selective with low toxicity.
  • pharmaceutically effective amount is meant an amount of a pharmaceutical compound or composition having a therapeutically relevant effect on a GI disease.
  • a therapeutically relevant effect relieves to some extent one or more symptoms of GI disease in a patient or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of GI disease, including, but not limited to, malaise, fever, abdominal pain and distress, malabsorption, diarrhea, blood loss through stool or vomit, weight loss, anemia, leukocytosis, abnormal endoscopic or radiologic appearance of GI tract.
  • GI diseases that may be treated by the methods and compositions of the present invention are diseases that adversely affect the GI tract, in particular, inflammatory, proliferatory and ulcerative diseases of the GI tract, including, but not limited to, peptic ulcer disease, colon cancer, and inflammatory bowel disorders such as colitis ulcerosa and Crohn's disease.
  • GI diseases that may be treated by the present invention are GI diseases that are caused by, or result in, altered PPAR activity in the GI tract.
  • Such GI diseases may be treated by administration of a PPAR modulator that restores PPAR activity in the GI tract partially or completely to normal levels present before the onset of the GI disease.
  • Such GI diseases that may be treated with a PPAR modulator according to this aspect of the invention may be identified based on the effect of the disease upon
  • GI diseases with reduced levels of PPAR activity in the GI tract are treated with modulators that activate PPARs, such as PPAR agonists or agents that enhance PPAR gene expression.
  • modulators that activate PPARs such as PPAR agonists or agents that enhance PPAR gene expression.
  • GI diseases with increased levels of PPAR activity in the GI tract are treated with modulators that inhibit PPARs, such as PPAR antagonists or agents that inhibit PPAR gene expression.
  • PPAR modulators useful in treating GI diseases according to the invention are small molecules and non-naturally occurring fatty acids that modulate the activity of one or more PPARs.
  • Such PPAR modulators include PPAR agonists and antagonists and agents that alter PPAR expression levels.
  • PPAR agonist is meant a compound or composition that, when combined with a PPAR, increases a reaction typical for the receptor, e.g., transcriptional regulation activity, as measured by an assay known to one skilled in the art, including, but not limited to, the co-transfection or cis-trans assays described or disclosed in U.S. Patent Nos. 4,981,784 and 5,071,773 and Lehmann, J. M. et al, J. Biol. Chem. 270: 12953-12956
  • a preferred PPAR ⁇ agonist is a thiazolidinedione compound, including, but not limited to, BRL 49653, troglitazone, pioglitazone, ciglitazone, WAY-120,744, englitazone, AD 5075, darglitazone, 15-Deoxy- D12,14 prostaglandin J2, and congeners, analogs, derivatives and pharmaceutically acceptable salts thereof.
  • BRL 49653 troglitazone
  • pioglitazone pioglitazone
  • ciglitazone WAY-120,744
  • englitazone AD 5075
  • darglitazone 15-Deoxy- D12,14 prostaglandin J2
  • congeners analogs, derivatives and pharmaceutically acceptable salts thereof.
  • a preferred PPAR ⁇ agonist is a fibrate compound including, but not limited to, gemfibrozil, fenofibrate, bezofibrate, clofibrate, ciprofibrate, and analogs, derivatives and pharmaceutically acceptable salts thereof.
  • Preferred PPAR ⁇ and ⁇ agonists include sulfur-substituted fatty acids and derivatives hereof, 5,8,11,14- eicosatetraynoic acid (ETYA).
  • Preferred PPAR ⁇ agonists include sulfur-substituted fatty acids and derivatives hereof, ETYA and compounds disclosed in U.S. Patent No.
  • an RXR ligand is used in place of or in addition to the PPAR agonist in the composition or method of this invention.
  • RXR ligand is meant a compound or composition that, when combined with RXR, increases the transcriptional regulation activity of the RXR/PPAR heterodimer, as measured by an assay known to one skilled in the art, including, but not limited to, d e co-transfection or cis-trans assays described or disclosed in U.S. Patent Nos.
  • RXR agonists that, when combined with RXR homodimers or heterodimers, increase the transcriptional regulation activity of both the RXR homodimers and heterodimers.
  • RXR antagonists that increase the transcriptional regulation activity of RXR/PPAR heterodimers while decreasing the transcriptional regulation activity of RXR homodimers, including, but not limited to, LG100754, z.e. (2E,4E,6Z)-3-methyl-7-[3- «-propoxy-5,6,7,8-tetrahydro-5,5,8,8- tetramethylnaphthalen-2-yl)-octa-2,4,6-trienoic acid, LG100823, i.e.
  • RXR and RAR i.e. pan agonists
  • RXR and RAR also includes compounds that activate RXR in a certain cellular context but not in others (i.e. partial agonists).
  • Compounds disclosed or described in the following articles, patents and patent applications that have RXR agonist activity are incorporated by reference herein: U.S. patents 5,399,586 and 5,466,861; WO96/05165; PCT/US95/16842; PCT/US95/16695; PCT/US93/10094; WO94/15901;
  • RXR specific ligands include, but are not limited to, LG100268 (i.e. 2-[l-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)-cyclopropyl]-pyridine-5-carboxylic acid) and LGD 1069 (i.e. 4-[(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-carbonyl]-benzoic acid), and congeners, analogs, derivatives and pharmaceutically acceptable salts thereof.
  • LG100268 i.e. 2-[l-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)-cyclopropyl]-pyridine-5-carboxylic acid
  • LGD 1069 i.e. 4-[(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-
  • LG100268 and LGD 1069 are disclosed in Boehm, M. F. et al, J. Med. Chem. 38(16): 3146-3155 (1994), incorporated by reference herein.
  • Pan agonists include, but are not limited to, ALRT 1057 (9-cis retinoic acid), and analogs, derivatives and pharmaceutically acceptable salts thereof.
  • PPAR antagonist is meant a compound or composition that, when combined with a PPAR, decreases a reaction typical for the receptor, e.g., transcriptional regulation activity, as measured by an assay known to one skilled in the art, including, but not limited to, the co-transfection or cis-trans assays described or disclosed in U.S. Patent Nos.
  • PPAR antagonists include any compound (e.g., an anti-PPAR antibody, etc.) that prevents or inhibits the association of a functional heterodimer by binding to one or both of the heterodimer partners.
  • a composition containing a pharmaceutically effective amount of a PPAR modulator according to the invention may be administered orally or systemically to a host.
  • it is administered orally or via the rectum.
  • the skilled artisan can determine the appropriate PPAR modulator(s) to use in any particular circumstance based upon the GI disease to be treated, the symptoms exhibited by the host to be treated, the level of PPAR activity in the GI tract of the host, and other factors well known to those of skill in the art.
  • This invention features a pharmaceutical composition for treating GI disease containing a pharmaceutically effective amount of a PPAR modulator and a pharmaceutically acceptable carrier adapted for a host, particularly a human, having a GI disease.
  • the composition is held within a container that includes a label stating to the effect that the composition is approved by the FDA in the United
  • This invention also features screening methods for identifying PPAR modulators that are useful for treating GI disease. These screening methods utilize cells derived from gastrointestinal tissue which express PPARs.
  • Figure 1 shows the expression levels of PPAR ⁇ 1 and PPAR ⁇ 2 in different human tissues.
  • the particular compound(s) that affects the disorders or conditions of interest can be administered to a patient either by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipient(s).
  • a therapeutically effective amount of an agent or agents such as these is administered.
  • a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient.
  • the compounds also can be prepared as pharmaceutically acceptable salts.
  • Examples of pharmaceutically acceptable salts include acid addition salts such as those containing hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, j ⁇ -toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, j ⁇ -toluenesulfonate, cyclohexylsulfamate and quinate.
  • Such salts can be derived using acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, -toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid.
  • acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, -toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid.
  • salts can be prepared by standard techniques. For example, the free base form of the compound is first dissolved in a suitable solvent such as an aqueous or aqueous-alcohol solution, containing the appropriate acid. The salt is then isolated by evaporating the solution. In another example, the salt is prepared by reacting the free base and acid in an organic solvent.
  • Carriers or excipients can be used to facilitate administration of the compound, for example, to increase the solubility of the compound.
  • carriers and excipients include calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects, the therapeutic index can be expressed as the ratio LD 50 /ED 50 .
  • Compounds that exhibit large therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosages for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED ⁇ with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Levels in plasma may be measured, for example, by HPLC.
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Suitable routes may include oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present invention in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes, then administered as described above. Liposomes are spherical lipid bilayers with aqueous interiors. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external microenvironment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. Additionally, due to their hydrophobicity, small organic molecules may be directly administered intracellularly. Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Liposomes may be used for encapsulated delivery. Agents intended to be administered via the rectum may be administered using techniques well known to those of ordinary skill in the art.
  • cells derived from gastrointestinal tissue are used to screen for PPAR modulators using a conventional approach that has been used with cells from non-gastrointestinal tissue to screen for mimics and modulators of several cellular signals (see, e.g. Rosen et al, J Med. Chem 38: 4855 (1995); Lehmann, et al, J. Biol. Chem. 270:12953-12956 (1995); U.S. Patent Nos. 4,981,784, 5,071,773, 5,298,429,
  • cells derived from gastrointestinal tissue which express one or more PPARs may be used to screen for PPAR modulators.
  • PPAR modulators include, but are not limited to, Caco-2 (ATCC No. HTB-37) and C2BBel (ATCC CRL-
  • the ability of a compound to act as a PPAR modulator is measured by the ability of the compound to alter the expression of one or more target genes whose expression is mediated by PPAR in the host cell used.
  • PPAR responsive target genes which may be used in the assay include genes which naturally occur in the host cell used, as well as genes which are engineered for PPAR responsiveness and transfected into the host cell.
  • the target gene used is a gene encoding luciferase which has been engineered for PPAR responsiveness.
  • compounds may be assayed for their ability to activate PPAR or to alter the activity of an activated PPAR.
  • level of expression of one or more PPAR-responsive target genes is measured both in the presence and absence of a test compound and the measurements are compared.
  • PPAR activators are identified as those compounds which alter the expression of a target gene in the same manner, but not necessarily to the same degree, as a known PPAR activator such as BRL 49653 or troglitazone.
  • the level of expression of one or more PPAR-responsive target genes is measured (1) in the presence of both an activator and a test compound, and (2) in the presence of the activator alone, and the measurements are compared.
  • Those compounds which alter the response of the target gene are identified as modulators of the PPAR activator.
  • Those compounds which increase the level of expression of a target gene in response to a PPAR activator are identified as potentiators of the activator and those which decrease the level of expression of a target gene in response to a PPAR activator are identified as inhibitors or antagonists of the activator.
  • Expression of a target gene can be measured at the level of transcription by measuring mRNA levels, or at the level of translation by measuring protein levels or protein activity.
  • Techniques which are well known in the art for measuring mRNA or protein levels can be used in the methods of the invention to measure the level of expression of a target gene.
  • Standard techniques for detecting and quantitating mRNA levels include, but are not limited to, Northern blot analysis, SI nuclease analysis, R ase protection and PCR.
  • Standard techniques for detecting and quantitating protein levels include, but are not limited to, Western blot analysis, ELISA, and activity assays for particular proteins such as enzymes and reporters, e.g. luciferase [E. Harlow et al, Antibodies: A Laboratory Manual.
  • Compounds identified by the methods of the invention may be used as drugs for modulating PPAR activity in the gastrointestinal tract as described herein.
  • Example l;ColorectaI Cancer and PPARs Colorectal cancer one of the most frequent cancers in the industrialized world, has been shown to be a paradigm for the multistep genetic basis of cancer '.
  • the intake of fatty acids is correlated with susceptibility for colon cancer 7'14 .
  • COX inducible cyclooxygenase
  • NSAIDs non-steroidal anti-inflammatory drugs
  • PPAR ⁇ is a nuclear receptor implicated in adipocyte differentiation and insulin sensitivity 16 " 20 .
  • Antidiabetic thiazolidinediones such as troglitazone and BRL-49,653 are high affinity synthetic ligands for PPAR ⁇ and improve insulin sensitivity and glucose homeostasis through the activation of PPAR ⁇ ".
  • the colon is the only part of the intestine showing high levels of PPAR ⁇ by Northern and Western blot analysis. Expression of PPAR ⁇ in colon is comparable to that in White Adipose tissue. Immunohistochemical staining of PPAR ⁇ in sections of normal mouse colon revealed that PPAR ⁇ is expressed both in epithelial cells and in the muscular layer, and most abundantly located in the nuclei.
  • PPAR ⁇ activators increase tumor multiplicity and size in the colon
  • mice treated with PPAR ⁇ activators have less differentiated tumors in the colon
  • Cytological abnormalities include cellular and nuclear pleiomorphism and loss of polarity.
  • Architectural abnormalities are the presence of intraglandular papillary projections and of cribriform and solid epithelial areas.
  • a cribriform growth pattern was seen in more than 50 % of the tumor area.
  • die presence of PPAR ⁇ was confirmed in adenocarcinomas in the colon of these C57BL/6J-APCmin/+ mice. Similar histological results were observed after troglitazone treatment.
  • PPAR ⁇ activators increase the level of ⁇ -catenin in the colon
  • PPAR ⁇ activation was also studied in vitro in the cultured human colon carcinoma cell line, HT-29.
  • HT-29 cells express high levels of PPAR ⁇ protein. Treatment with PPAR ⁇ activators did not change the levels of PPAR ⁇ in these cells.
  • PPAR ⁇ was expressed at a high level in the colon. Much lower levels of PPAR ⁇ were present in the rest of the intestine. The correlation between high levels of PPAR ⁇ and intestinal regions with increased tumor formation supports that activation of PPAR ⁇ in the colon influences tumor initiation and/or development in the C57BL/6J-APC M " / + mouse model.
  • Troglitazone and BRL-49,653 were obtained from Dr. A. Saltiel (Parke-Davis) and
  • Goat anti-Cox-2 (sc-1746), goat anti- ⁇ -catenin (sc-1496) were purchased from Santa-Cruz (Santa-Cruz, USA) and used at a 1 :500 dilution.
  • mice were obtained at 5 weeks of age from the mice
  • mice were treated for 8 weeks (starting at 6 weeks of age) with BRL-49,653 (20 mg/kg body weight/day) or troglitazone (150 mg/kg body weight/day) mixed with the standard show. Control mice were fed a diet without drug.
  • mice were sacrified by decapitation under light ether anesthesia.
  • the entire intestine was quickly removed, divided in 5 equal sections from duodenum to the rectum, opened and examined under a magnification dissecting microscope (x5) to count the tumors.
  • the tumor diameter was measured with a calibrated eye reticle.
  • HT-29 cells were grown in McCoy's medium supplemented with 10% fetal calf serum, 50 mg/ml streptomycin and 50u/ml penicillin. The cells were subcultured when they were 80% confluent by using 0.5 % trypsin and seeded at a density of 5x10 4 cells/cm 2 .
  • RNA and protein analysis Isolation of total RNA, Northern blot analysis, protein preparation, and immunoblotting were performed as described 30 - 32 . Immunodetection with secondary peroxidase conjugated antibody and chemilluminescence was performed according to the manufacturer's protocol (ECL, Amersham, UK).
  • PPAR ⁇ activation of PPAR ⁇ by two different synthetic agonists increased the frequency and size and decreased the differentiation of colon tumors in an animal model susceptible to intestinal neoplasia, i.e., C57BL/6J-APC M,n / + mice. Tumor frequency was increased in the colon, whereas no change in frequency of the tumors was observed in the small intestine. This correlates with the colon-restricted expression pattern of PPAR ⁇ mRNA and protein.
  • Wnt/wingless/APC pathway which increase free ⁇ -catenin levels and enhance the transcriptional activity of the ⁇ -catenin-Tcf/Lefl transcription complex, have been shown to frequently underly the development of colon cancer.
  • PPAR ⁇ activation modifies the development of colon cancer. That the PPAR ⁇ expression pattern coincides with the regions where PPAR ⁇ activation may be associated with cancer development strongly supports that PPAR ⁇ is involved in the enhancement of colon tumorigenesis in C57BL/6J-APC M " / + mice.
  • Example 2 Inflammatory Diseases of the GI Tract and PPARs Inflammatory cells such as blood monocytes express very low levels of PPAR ⁇ in the resting or inactive state (See, e.g., Ricote, et al., Nature 391 :79-82 (1998)). The level of expression of PPAR ⁇ rises significantly when monocytes are provoked to produce an inflammatory response as when stimulated with interferon ⁇ . The administration of a PPAR ⁇ modulator at this time, such as 15-deocy-D12,14 prostaglandin J2, suppresses inflammatory responses.
  • a PPAR ⁇ modulator such as 15-deocy-D12,14 prostaglandin J2
  • a PPAR ⁇ modulator can suppress the expression of inducible nitric oxide synthetase, the expression of gelatinase B, and the production of inflammatory cytokines such as tumor necrosis factor ⁇ (TNF- ⁇ ) by human monocytes (See, e.g., Jiang, et al., Nature 391 :82-86 (1998)).
  • PPAR ⁇ modulators can be used to treat the inflammatory diseases of the GI tract.

Abstract

L'invention a trait à des méthodes thérapeutiques et aux compositions afférentes permettant de traiter un sujet atteint de troubles gastro-intestinaux, lesquelles méthodes consistent à administrer à celui-ci une composition contenant une quantité efficace du point de vue pharmaceutique d'un modulateur du récepteur activé de la prolifération des peroxysomes (PPAR), notamment un modulateur du PPARη. Elle porte également sur des techniques de criblage aux fins de l'identification de modulateurs du PPAR, lesquelles techniques font intervenir des cellules dérivées du tissu gastro-intestinal exprimant des PPAR.
PCT/US1998/005852 1997-03-26 1998-03-25 Traitement de troubles gastro-intestinaux au moyen de modulateurs du recepteur active de la proliferation des peroxysomes (ppar) WO1998043081A1 (fr)

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WO2000053563A1 (fr) * 1999-03-11 2000-09-14 Nuclear Receptor Research Limited Nouveaux ligands de recepteurs nucleaires ppar
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WO2001007066A2 (fr) * 1999-07-23 2001-02-01 The University Of Dundee Methodes de traitement et de criblage de medicaments
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WO2002080899A1 (fr) * 2001-03-30 2002-10-17 Eisai Co., Ltd. Agent de traitement de maladie digestive
WO2003046580A1 (fr) * 2001-11-21 2003-06-05 Rowett Research Institute Technique de criblage de medicaments candidats pour le traitement de maladies inflammatoires
WO2005093423A2 (fr) * 2004-03-26 2005-10-06 Bayer Healthcare Ag Diagnostic et traitement de maladies associees au recepteur active de la proliferation des peroxysomes alpha (ppara)
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WO2008104305A1 (fr) * 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Pygm utilisables comme marqueurs biologiques pour les modulateurs ppara
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