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US 20060069 161A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0069.161 A1 Lee et al. (43) Pub. Date: Mar. 30, 2006 (54) METHODS AND REAGENTS FOR THE Related U.S. Application Data TREATMENT OF METABOLIC DSORDERS (60) Provisional application No. 60/584,380, filed on Jun. (75) Inventors: Margaret S. Lee, Middleton, MA (US); 30, 2004. Provisional application No. 60/649,329, Grant R. Zimmermann, Somerville, filed on Feb. 2, 2005. MA (US); Alyce L. Finelli, Framingham, MA (US); Daniel Grau, Publication Classification Cambridge, MA (US); Curtis Keith, Boston, MA (US); M. James Nichols, (51) Int. Cl. Boston, MA (US) A6II 3L/92 (2006.01) A6II 38/28 (2006.01) Correspondence Address: A6II 3/56 (2006.01) CLARK & ELBNG LLP (52) U.S. Cl. .............................. 514/570; 514/571; 514/3; 101 FEDERAL STREET 514/369; 514/340; 514/355; BOSTON, MA 02110 (US) 514/171 (73) Assignee: CombinatoRx, Inc., Boston, MA (US) (57) ABSTRACT (21) Appl. No.: 11/171,566 The invention features compositions, methods, and kits for the treatment of metabolic disorders such as diabetes and (22) Filed: Jun. 30, 2005 obesity. Patent Application Publication Mar. 30, 2006 Sheet 1 of 3 US 2006/0069.161 A1 F.G. 1 Chow HF Pio 6 DF Bez BezIDF Patent Application Publication Mar. 30, 2006 Sheet 2 of 3 US 2006/00691.61 A1 FIG 2 300 250 2 O O 150 100 50 ChoW HF Pio 6 DF Bez Bez/DF Patent Application Publication Mar. 30, 2006 Sheet 3 of 3 US 2006/0069.161 A1 FIG. 3 60 4.O 2 O Chow HF Pio 6 DF Bez Bez/OF US 2006/0069 161 A1 Mar. 30, 2006 METHODS AND REAGENTS FOR THE debilitating side effects. Accordingly, patients diagnosed TREATMENT OF METABOLIC DSORDERS with or at risk of having type 2 diabetes are often advised to adopt a healthier lifestyle, including loss of weight, change CROSS-REFERENCE TO RELATED in diet, exercise, and moderate alcohol intake. Such lifestyle APPLICATIONS changes, however, are not sufficient to reverse the vascular and organ damages caused by diabetes. 0001. This application claims benefit from U.S. Ser. No. 60/584,380, filed Jun. 30, 2004, and U.S. Ser. No. 60/649, 0007 Given that the strategies currently available for the 329, filed Feb. 2, 2005, each of which is hereby incorporated management of diabetes are suboptimal, there is a compel by reference. ling need for treatments that are more effective and are not associated with such debilitating side-effects. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0002 The invention relates to the treatment, prevention, and reduction of metabolic disorders, such as diabetes and 0008. The present invention features compositions, meth obesity. ods, and kits for treating, preventing, and reducing meta bolic disorders. This invention is particularly useful for 0003. As the levels of blood glucose rise postprandially, treating patients having or at risk of having any condition insulin is secreted and stimulates cells of the peripheral that is characterized by a state of hyperglycemia, which may tissues (skeletal muscles and fat) to actively take up glucose be caused, for example, by an alteration in the insulin from the blood as a source of energy. Loss of glucose signaling pathway (e.g., a reduction in insulin production, homeostasis as a result of faulty insulin secretion or action resistance to insulin, or both). Exemplary disorders ame typically results in metabolic disorders such as diabetes, nable to treatment according to this invention are obesity, which may be co-triggered or further exacerbated by obesity. diabetes (e.g., type 1 diabetes, type 2 diabetes, maturity Because these conditions are often fatal, strategies to restore onset diabetes of the young (MODY), and gestational dia adequate glucose clearance from the bloodstream are betes), Satiety, endocrine deficiencies of aging, and any of required. their associated complications (e.g., Syndrome X, diabetic 0004 Although diabetes may arise secondary to any retinopathy, diabetic nephropathy, diabetic neuropathy, condition that causes extensive damage to the pancreas (e.g., peripheral vascular disease, hyperlipidemia, hypertension, pancreatitis, tumors, administration of certain drugs such as atherosclerosis, and coronary heart disease). corticosteroids or pentamidine, iron overload (e.g., hemo chromatosis), acquired or genetic endocrinopathies, and 0009. In a first aspect, the invention features a composi Surgical excision), the most common forms of diabetes tion that includes (a) bezafibrate or an analog thereof, and typically arise from primary disorders of the insulin signal (b) diflunisal or an analog thereof, wherein the bezafibrate ing system. There are two major types of diabetes, namely and diflunisal are present in amounts that, when adminis type 1 diabetes (also known as insulin dependent diabetes tered to a patient, are sufficient to treat, prevent, or reduce a (IDDM)) and type 2 diabetes (also known as insulin inde metabolic disorder (e.g., diabetes or obesity). Exemplary pendent or non-insulin dependent diabetes (NIDDM)), combinations are bezafibrate and diflunisal; bezafibrate and which share common long-term complications in spite of bismuth subsalicylate; bezafibrate and nimosulide; bezafi their different pathogenic mechanisms. brate and oxaprozin; bezafibrate and diclofenac; bezafibrate and sundilac.; bezafibrate and ibuprofen; clofibrate and 0005 Type 1 diabetes, which accounts for approximately diflunisal; clofibrate and bismuth subsalicylate; clofibrate 10% of all cases of primary diabetes, is an organ-specific and nimosulide; clofibrate and oxaprozin, clofibrate and autoimmune disease characterized by the extensive destruc diclofenac; clofibrate and sundilac, clofibrate and ibuprofen; tion of the insulin-producing beta cells of the pancreas. The clofibrinc acid and diflunisal; clofibric acid and bismuth consequent reduction in insulin production inevitably leads subsalicylate; clofibric acid and nimosulide; clofibric acid to the deregulation of glucose metabolism. While the admin and oxaprozin: clofibric acid and diclofenac; clofibric acid istration of insulin provides significant benefits to patients and sundilac; clofibric acid and ibuprofen; clinofibrate and suffering from this condition, the short serum half-life of diflunisal; clinofibrate and bismuth subsalicylate; clinofi insulin is a major impediment to the maintenance of nor brate and nimosulide; clinofibrate and oxaprozin, clinofi moglycemia. An alternative treatment is islet transplanta brate and diclofenac; clinofibrate and sundilac, clinofibrate tion, but this strategy has been associated with limited and ibuprofen; gemfibrozil and diflunisal; gemfibrozil and SCCCSS, bismuth Subsalicylate, gemfibrozil and nimosulide; gemfi 0006 Type 2 diabetes, which affects a larger proportion brozil and Oxaprozin, gemfibrozil and diclofenac; gemfi of the population, is characterized by a deregulation in the brozil and sundilac; and gemfibrozil and ibuprofen. secretion of insulin and/or a decreased response of periph 0010. In a second aspect, the invention features a com eral tissues to insulin, i.e., insulin resistance. While the position that includes (a) bezafibrate or an analog thereof. pathogenesis of type 2 diabetes remains unclear, epidemio and (b) cinnamic acid or an analog thereof, wherein the logic studies suggest that this form of diabetes results from bezafibrate and diflunisal are present in amounts that, when a collection of multiple genetic defects or polymorphisms, administered to a patient, are sufficient to treat, prevent, or each contributing its own predisposing risks and modified by reduce a metabolic disorder. environmental factors, including excess weight, diet, inac tivity, drugs, and excess alcohol consumption. Although 0011 Exemplary bezafibrate analogs are binifibrate, various therapeutic treatments are available for the manage ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, ment of type 2 diabetes, they are associated with various fenofibrate, or gemfibrozil. US 2006/0069 161 A1 Mar. 30, 2006 0012. In either of the foregoing aspects, the composition clofibric acid and diclofenac; clofibric acid and sundilac, may include a third agent selected from the group consisting clofibric acid and ibuprofen; clinofibrate and diflunisal; of Sulfonylureas, non-sulfonylurea secretagogues, insulin, clinofibrate and bismuth subsalicylate; clinofibrate and insulin analogs, glucagon-like peptides, exendin-4 polypep nimosulide; clinofibrate and Oxaprozin; clinofibrate and tides, beta 3 adrenoceptor agonists, PPAR agonists, dipep diclofenac; clinofibrate and sundilac, clinofibrate and ibu tidyl peptidase IV inhibitors, biguanides, alpha-glucosidase profen; gemfibrozil and diflunisal; gemfibrozil and bismuth inhibitors, immunomodulators, statins and statin-containing Subsalicylate; gemfibrozil and nimosulide; gemfibrozil and combinations, angiotensin converting enzyme inhibitors, oxaprozin, gemfibrozil and diclofenac; gemfibrozil and Sun adeno sine A1 receptor agonists, adenosine A2 receptor dilac, and gemfibrozil and ibuprofen. agonists, aldosterone antagonists, alpha 1 adrenoceptor antagonists, alpha 2 adrenoceptor agonists, alpha 2 adreno 0015 The invention also features a method for treating, ceptor agonists, angiotensin receptor antagonists, antioxi preventing, or reducing a metabolic disorder in a patient in dants, ATPase inhibitors, atrial peptide agonists, beta need thereof by administering to the patient (i) bezafibrate or adrenoceptor antagonists, calcium channel agonists, calcium an analog thereof,
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    US009447027B2 (12) United States Patent (10) Patent No.: US 9.447,027 B2 Milan et al. (45) Date of Patent: Sep. 20, 2016 (54) TREATING LONG QT SYNDROME 2004/O1972.71 A1* 10, 2004 Kunka et al. ................... 424/45 2006/0173058 A1* 8, 2006 Brown .................... CO7C 65/05 514,381 (75) Inventors: Es l, St. MS 2006/0173508 A1* 8, 2006 Stone ................. A61N 1,36085 aVId S. Peal, SomerV11 le. (US) 607/40 (73) Assignee: The General Hospital Corporation, FOREIGN PATENT DOCUMENTS Boston, MA (US) JP 11209328 A1 * 8, 1999 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 86 days. Nademanee, K. et al., Annals of the New York Academy of Sciences vol. 522, pp. 536-552, published 2006.* (21) Appl. No.: 13/822,264 Chouabe, C. et al., Molecular Pharmacology vol. 54 pp. 696-703, published 1998.* (22) PCT Filed: Oct. 20, 2011 Nishizawa, S., et al., (American Journal of Emergency Medicine vol. 27, pp. 1167.e1-1167.e3, published Nov. 2009).* (86). PCT No.: PCT/US2011/057087 Nishizawa et al., (American Journal of Emergency Medicine vol. 27, pp. 1167.el -1167.e3, published Nov. 2009).* S 371 (c)(1), Nishizawa et al (American Journal of Emergency Medicine vol. 27. (2), (4) Date: Jul. 22, 2013 pp. 1167.e1-1167.e3, published Nov. 2009).* Anderson et al., “Most LQT2 Mutations Reduce Kv11.1 (hERG) Current by a Class 2 (Trafficking-Deficient) Mechanism.” Circula (87) PCT Pub. No.: WO2012/054718 tion 113:365-373, 2006, 10 pages.