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(12) Patent Application Publication (10) Pub. No.: US 2016/0235807 A1 SHALUBHA (43) Pub US 2016O235807A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0235807 A1 SHALUBHA (43) Pub. Date: Aug. 18, 2016 (54) AGONSTS OF GUANYLATE CYCLASE Publication Classification USEFUL FOR DOWNREGULATION OF PRO-NFLAMMLATORY CYTOKINES (51) Int. Cl. A638/10 (2006.01) (71) Applicant: SYNERGY PHARMACEUTICALS, A619/00 (2006.01) INC., New York, NY (US) A6II 45/06 (2006.01) A613 L/40 (2006.01) (72) Inventor: Kunwar SHAILUBHAI, Audubon, PA A 6LX3/5377 (2006.01) (US) (52) U.S. Cl. CPC ................. A61K 38/10 (2013.01); A61K 31/40 (21) Appl. No.: 15/026,560 (2013.01); A61 K3I/5377 (2013.01); A61 K (22) PCT Fled: Oct. 9, 2014 45/06 (2013.01); A61 K9/0053 (2013.01) (57) ABSTRACT (86) PCT NO.: PCT/US1.4/S9914 This invention provides a method to prevent, control, and/or S371 (c)(1), treat an inflammatory disease or disorder by administering at (2) Date: Mar. 31, 2016 least one agonist of guanalyte cyclase receptor, or pharma ceutical compositions thereof, either alone or either concur Related U.S. Application Data rently or sequentially with another compound or an active (60) Provisional application No. 61/888,744, filed on Oct. agent used to treat the disease or disorder, and/or with an 9, 2013. inhibitor of c(GMP-dependent phosphodieasterases. Patent Application Publication Aug. 18, 2016 Sheet 1 of 31 US 2016/0235807 A1 F–FFT H–FTT Patent Application Publication Aug. 18, 2016 Sheet 2 of 31 US 2016/0235807 A1 rt of c) ce. c. c. ... 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Sesay, añej9 Sisis is aise S8iaak3 Patent Application Publication Aug. 18, 2016 Sheet 31 of 31 US 2016/0235807 A1 |||- | ººººdS | }*******uopeano US 2016/0235807 A1 Aug. 18, 2016 AGONSTS OF GUANYLATE CYCLASE dithiocarbamate (PTDC). In a further embodiment, the c-Src USEFUL FOR DOWNREGULATION OF tyrosine kinase inhibitor is KX2-391. PRO-NFLAMMLATORY CYTOKINES 0005. The invention provides a method for preventing or treating a condition by administering to a subject in need of a CROSS REFERENCE TO RELATED therapeutically effective amount of the composition of the APPLICATIONS invention. For example, the condition is colitis, ulcerative 0001. This application claims the benefit of U.S. Provi colitis, Crohn's disease, irritable bowel syndrome (IBS), non sional Application No. 61/888,744, filed Oct. 9, 2013, which ulcer dyspepsia, chronic intestinal pseudo-obstruction, func is herein incorporated by reference in its entirety for all pur tional dyspepsia, colonic pseudo-obstruction, duodenogas poses. tric reflux, constipation, constipation associated with use of opiate pain killers, post-Surgical constipation, IBS-associated FIELD OF THE INVENTION constipation, constipation associated with neuropathic disor ders, gastroesophageal reflux disease (GERD), Celiac dis 0002 The present invention relates to the therapeutic use ease, gastroparesis, heartburn, poor gastrointestinal motility, of guanylate cyclase C (GC-C) agonists for downregulation congestive heart failure, hypertension, benign prostatic of pro-inflammatory cytokines. The agonists may be used hyperplasia (BPH), gastrointestinal cancer, lung cancer, blad either alone or either concurrently or sequentially with addi der cancer, liver cancer, salivary gland cancer, skin cancer, tional active agents to prevent or downregulate NF-KB acti colon cancer, bronchitis, tissue inflammation, organ inflam Vation and pro-inflammatory cytokines in the human body. mation, respiratory inflammation, asthma, COPD, lipid The GC-C agonists may be used to prevent or treat colitis, metabolism disorder, biliary disorder, cardiovascular disease, including dextran sulphate sodium (DSS) induced colitis, obesity or an endocrine disorder. ulcerative colitis, Crohn's disease, colon cancer, and/or any 0006. The invention provides a method of treating or alle Swelling or inflammation of the large intestine. viating a symptom of a NF-kB mediated inflammation by BACKGROUND OF THE INVENTION administering to a subject in need thereofan effective amount of a GCRA peptide or pharmaceutical composition thereof. 0003. The human chronic inflammatory bowel diseases The invention provides that the amount is effective to inhibit (IBD), Crohn's disease (CD) and ulcerative colitis (UC), NF-KB activation, thus treating or alleviating a symptom of affect over one million Americans. While the etiology of an inflammatory disorder or a NF-kB mediated inflamma these disorders remains unknown, contributing factors tion. For example, the inflammatory disorder or a NF-KB include a poorly regulated immune response against the mediated inflammation is colitis, ulcerative colitis, Crohn's enteric microbiota in a genetically predisposed individual. disease, irritable bowel syndrome (IBS), tissue inflammation, There is currently no cure for IBD and existing therapies such organ inflammation, kidney inflammation, gastrointestinal as corticosteroids, 5-aminosalicylates, and immunomodula system inflammation, necrotizing enterocolitis, pancreatic tory agents (6-mercaptopurine, methotrexate) are of limited inflammation, lung inflammation, respiratory inflammation, effectiveness, have the potential for side effects, and/or are asthma, COPD or skin inflammation. designed to non-specifically reduce intestinal inflammation. 0007. The invention further provides a method of modu As a result of the burden of their clinical symptoms and side lating NF-KB induction in a cell by contacting the cell with an effects of medications, most patients with IBD have a signifi effective amount of a GCRA peptide orpharmaceutical com cantly impaired quality of life.
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