US00779531 OB2 (12) United States Patent (10) Patent No.: US 7,795,310 B2 Lee et al. (45) Date of Patent: Sep. 14, 2010 (54) METHODS AND REAGENTS FOR THE WO WO 2005/025673 3, 2005 TREATMENT OF METABOLIC DISORDERS OTHER PUBLICATIONS (75) Inventors: Margaret S. Lee, Middleton, MA (US); Tenenbaum et al., “Peroxisome Proliferator-Activated Receptor Grant R. Zimmermann, Somerville, Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in MA (US); Alyce L. Finelli, Patients With Coronary Artery Disease'. Circulation, 2004, pp. 2197 Framingham, MA (US); Daniel Grau, 22O2.* Shen et al., “Effect of gemfibrozil treatment in sulfonylurea-treated Cambridge, MA (US); Curtis Keith, patients with noninsulin-dependent diabetes mellitus'. The Journal Boston, MA (US); M. James Nichols, of Clinical Endocrinology & Metabolism, vol. 73, pp. 503-510, Boston, MA (US) 1991 (see enclosed abstract).* International Search Report from PCT/US2005/023030, mailed Dec. (73) Assignee: CombinatoRx, Inc., Cambridge, MA 1, 2005. (US) Lin et al., “Effect of Experimental Diabetes on Elimination Kinetics of Diflunisal in Rats.” Drug Metab. Dispos. 17:147-152 (1989). (*) Notice: Subject to any disclaimer, the term of this Abstract only. patent is extended or adjusted under 35 Neogi et al., “Synthesis and Structure-Activity Relationship Studies U.S.C. 154(b) by 0 days. of Cinnamic Acid-Based Novel Thiazolidinedione Antihyperglycemic Agents.” Bioorg. Med. Chem. 11:4059-4067 (21) Appl. No.: 11/171,566 (2003). Vessby et al., “Effects of Bezafibrate on the Serum Lipoprotein Lipid and Apollipoprotein Composition, Lipoprotein Triglyceride Removal (22) Filed: Jun. 30, 2005 Capacity and the Fatty Acid Composition of the Plasma Lipid Esters.” Atherosclerosis 37:257-269 (1980). Abstract only. (65) Prior Publication Data Windholz et al., eds., “Abstract No. 4866. The Merck Index. 10" ed., US 2006/OO69 161A1 Mar. 30, 2006 p. 723-724. 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(52) U.S. Cl. ........................ 514/568; 514/571; 514/866 Communication from the State Intellectual Property Office of the (58) Field of Classification Search ................. 514/568, People's Republic of China for Application No. 2005800289684 514/571,866 with English translation (issued Jul. 17, 2009), (pp. 1-16). See application file for complete search history. Yang et al., “The Comparison of Treatment of Type 2 Diabetes Mellitus Complicated with Hyperlipemia with Bezafibrate and (56) References Cited Pravastatin Sodium', Shanghai Medical Journal 21:478-480, 1998. U.S. PATENT DOCUMENTS * cited by examiner 6, 194.454 B1 2/2001 Dow .......................... 514,522 Primary Examiner Kevin Weddington 6,500,823 B1* 12/2002 Literati Nagy et al. ... 514/231.5 (74) Attorney, Agent, or Firm—Clark & Elbing LLP 6,576,256 B2 6/2003 Liang et al. 6.593,347 B2 * 7/2003 Bandarage et al. .......... 514,327 (57) ABSTRACT 2002/0016293 A1 2/2002 Ratain et al. ................... 514/9 The invention features compositions, methods, and kits for FOREIGN PATENT DOCUMENTS the treatment of metabolic disorders such as diabetes and WO WOO3,059294 T 2003 obesity. WO WOO3,082283 10, 2003 WO WO 2004/052362 6, 2004 6 Claims, 3 Drawing Sheets U.S. Patent Sep. 14, 2010 Sheet 1 of 3 US 7,795,310 B2 FIG. 1 U.S. Patent Sep. 14, 2010 Sheet 2 of 3 US 7,795,310 B2 FIG 2 300 250 2 O O 150 100 50 ChoW HF Pio 6 DF Bez Bez/DF U.S. Patent Sep. 14, 2010 Sheet 3 of 3 US 7,795,310 B2 FIG. 3 60 4. O 2 O Chow HF Pio 6 DF Bez BezIDF US 7,795,310 B2 1. 2 METHODS AND REAGENTS FOR THE Given that the strategies currently available for the man TREATMENT OF METABOLIC DSORDERS agement of diabetes are suboptimal, there is a compelling need for treatments that are more effective and are not asso CROSS-REFERENCE TO RELATED ciated with such debilitating side-effects. APPLICATIONS SUMMARY OF THE INVENTION This application claims benefit from U.S. Ser. No. 60/584, 380, filed Jun. 30, 2004, and U.S. Ser. No. 60/649,329, filed The present invention features compositions, methods, and Feb. 2, 2005, each of which is hereby incorporated by refer kits for treating, preventing, and reducing metabolic disor CCC. 10 ders. This invention is particularly useful for treating patients having or at risk of having any condition that is characterized BACKGROUND OF THE INVENTION by a state of hyperglycemia, which may be caused, for example, by an alteration in the insulin signaling pathway The invention relates to the treatment, prevention, and (e.g., a reduction in insulin production, resistance to insulin, reduction of metabolic disorders, such as diabetes and obe 15 or both). Exemplary disorders amenable to treatment accord sity. ing to this invention are obesity, diabetes (e.g., type 1 diabe As the levels of blood glucose rise postprandially, insulin is tes, type 2 diabetes, maturity-onset diabetes of the young secreted and stimulates cells of the peripheral tissues (skeletal (MODY), and gestational diabetes), satiety, endocrine defi muscles and fat) to actively take up glucose from the blood as ciencies of aging, and any of their associated complications a source of energy. Loss of glucose homeostasis as a result of (e.g., Syndrome X, diabetic retinopathy, diabetic nephropa faulty insulin secretion or action typically results in metabolic thy, diabetic neuropathy, peripheral vascular disease, hyper disorders such as diabetes, which may be co-triggered or lipidemia, hypertension, atherosclerosis, and coronary heart further exacerbated by obesity. Because these conditions are disease). often fatal, strategies to restore adequate glucose clearance In a first aspect, the invention features a composition that from the bloodstream are required. 25 includes (a) bezafibrate or an analog thereof, and (b) Although diabetes may arise secondary to any condition diflunisal or an analog thereof, wherein the bezafibrate and that causes extensive damage to the pancreas (e.g., pancreati diflunisal are present in amounts that, when administered to a tis, tumors, administration of certain drugs such as corticos patient, are sufficient to treat, prevent, or reduce a metabolic teroids or pentamidine, iron overload (e.g., hemochromato disorder (e.g., diabetes or obesity). Exemplary combinations sis), acquired or genetic endocrinopathies, and Surgical 30 are bezafibrate and diflunisal; bezafibrate and bismuth Sub excision), the most common forms of diabetes typically arise salicylate; bezafibrate and nimosulide; bezafibrate and from primary disorders of the insulin signaling system. There oxaprozin, bezafibrate and diclofenac; bezafibrate and Sun are two major types of diabetes, namely type 1 diabetes (also dilac.; bezafibrate and ibuprofen; clofibrate and diflunisal; known as insulin dependent diabetes (IDDM)) and type 2 clofibrate and bismuth subsalicylate; clofibrate and nimo diabetes (also known as insulin independent or non-insulin 35 sulide; clofibrate and oxaprozin; clofibrate and diclofenac: dependent diabetes (NIDDM)), which share common long clofibrate and Sundilac; clofibrate and ibuprofen; clofibrinc term complications in spite of their different pathogenic acid and diflunisal; clofibric acid and bismuth subsalicylate: mechanisms. clofibric acid and nimosulide; clofibric acid and oxaprozin, Type 1 diabetes, which accounts for approximately 10% of clofibric acid and diclofenac; clofibric acid and sundilac, all cases of primary diabetes, is an organ-specific autoim 40 clofibric acid and ibuprofen; clinofibrate and diflunisal; cli mune disease characterized by the extensive destruction of nofibrate and bismuth subsalicylate; clinofibrate and nimo the insulin-producing beta cells of the pancreas. The conse sulide; clinofibrate and oxaprozin; clinofibrate and quent reduction in insulin production inevitably leads to the diclofenac; clinofibrate and Sundilac; clinofibrate and ibupro deregulation of glucose metabolism. While the administra fen, gemfibrozil and diflunisal; gemfibrozil and bismuth sub tion of insulin provides significant benefits to patients suffer 45 salicylate; gemfibrozil and nimosulide; gemfibrozil and ing from this condition, the short serum half-life of insulin is oxaprozin, gemfibrozil and diclofenac; gemfibrozil and Sun a major impediment to the maintenance of normoglycemia. dilac, and gemfibrozil and ibuprofen. An alternative treatment is islet transplantation, but this strat In a second aspect, the invention features a composition egy has been associated with limited Success. that includes (a) bezafibrate or an analog thereof; and (b) Type 2 diabetes, which affects a larger proportion of the 50 cinnamic acid or an analog thereof, wherein the beZafibrate population, is characterized by a deregulation in the secretion and diflunisal are present in amounts that, when administered of insulin and/or a decreased response of peripheral tissues to to a patient, are sufficient to treat, prevent,