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(12) Patent Application Publication (10) Pub. No.: US 2015/0265555 A1 BARON Et Al US 20150265555A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0265555 A1 BARON et al. (43) Pub. Date: Sep. 24, 2015 (54) CHEMOSENSORY RECEPTOR Publication Classification LGAND-BASED THERAPES (51) Int. Cl. (71) Applicant: Elcelyx Therapeutics, Inc., San Diego, A613 L/55 (2006.01) CA (US) A6II 45/06 (2006.01) (52) U.S. Cl. (72) Inventors: Alain D. BARON, San Diego, CA (US); CPC ............... A61K 31/155 (2013.01); A61K 45/06 Nigel R.A. BEELEY, Solana Beach, CA (2013.01) (US); Mark S. FINEMAN, San Diego, CA (US) (57) ABSTRACT (21) Appl. No.: 14/733,750 Provided herein are methods for treating conditions associ 1-1. ated with a chemosensory receptor, including diabetes, obe (22) Filed: Jun. 8, 2015 sity, and other metabolic diseases, disorders or conditions by Related U.S. Application Dat administrating a composition comprising a chemosensory e pplication Uata receptor ligand, Such as a bitter receptor ligand. Also provided (63) Continuation of application No. 13/978,514, filed on herein are chemosensory receptor ligand compositions, Sep. 18, 2013, now Pat. No. 9,050,292, filed as appli- including bitter receptor ligand compositions, and methods cation No. PCT/US2012/020548 on Jan. 6, 2012. for the preparation thereof for use in the methods of the (60) Provisional application No. 61/430.914, filed on Jan. present invention. Also provided herein are compositions 7, 2011. comprising metformin and salts thereof and methods of use. Patent Application Publication Sep. 24, 2015 Sheet 1 of 2 US 2015/0265555 A1 FIG. 1 Base-coffected a PYY tota Baselite-corrected ea Pi active -o- Contro: a. -- Bitter S 6 s 3. 4 2 2 d, O -2 -3 3. 6 a -3 3. s 2 50 Ere (min) Tire mir) AUC 27% Difference AUC 89% Difference p=0.14 p=0.07 Patent Application Publication Sep. 24, 2015 Sheet 2 of 2 US 2015/0265555 A1 FIG 2 Baseline-corrected L-cell Output index 2OOO 1 5 O O s & US 2015/0265555 A1 Sep. 24, 2015 CHEMOSENSORY RECEPTOR (MeridiaR), taken off the market in Europe and the USA, LGAND-BASED THERAPES decreases appetite by inhibiting deactivation of the neu rotransmitters norepinephrine, serotonin, and dopamine CROSS-REFERENCE Undesirable side-effects, including effects on blood pressure, have been reported with these drugs. (See, e.g., “Prescription 0001. This application is a continuation of U.S. patent Medications for the Treatment of Obesity.” NIH Publication application Ser. No. 13/978,514, filed Sep. 18, 2013, which is No. 07-4191, December 2007). Surgical treatments, includ a National Phase Entry of PCT Application No. PCT/ ing gastric bypass Surgery and gastric banding, are available, US2012/020548, filed Jan. 6, 2012, which claims the benefit but only in extreme cases. These procedures can be danger of U.S. Provisional Application No. 61/430.914, filed Jan. 7, ous, and furthermore may not be appropriate options for 2011, each of which is incorporated herein by reference. patients with more modest weight loss goals. BACKGROUND OF THE INVENTION Enteroendocrine Cells and Chemosensory Receptor Ligands 0002. Despite the longstanding, massive, effort to develop 0006 Certain intestinal cells, L cells, have been reported effective treatments for diabetes, metabolic syndrome, obe to produce GLP-1 in response to glucose, fat and amino acid sity, overweight and related metabolic conditions, the number stimulation. These and other such “enteroendocrine cells' of people worldwide who suffer from them is rapidly grow also reportedly produce other hormones involved in pro ing. These conditions result in numerous medical complica cesses relating to glucose and fuel metabolism, including tions, a lowered quality of life, shortened lifespan, lost work oxyntomodulin, reported to ameliorate glucose intolerance productivity, a strain on medical systems, and a burden on and suppress appetite, PYY (peptide YY), also observed to medical insurance providers that translates into increased Suppress appetite, CCK (cholecystokinin), which reportedly costs for all. Additionally, maintenance of health, including stimulates the digestion of fat and protein and also reduces healthy body weight and healthy blood glucose levels is desir food intake, GLP-2, which reportedly induces gut cell prolif able. eration, and GIP (gastric inhibitory polypeptide, also called 0003 Type II diabetes treatments in use or development glucose-dependent insulinotropic peptide), an incretin are designed to lower blood glucose levels. They include secreted from the intestinal K cells that has been observed to mimetics of GLP-1 (glucagon-like peptide-1), a hormone that augment glucose-dependent insulin secretion. (See, e.g., plays a key role in regulating insulin, glucose and hunger. Jang, et al., 2007, “Gut-expressed gustducin and taste recep Examples of mimetics are the GLP-1 receptor agonist, tors regulate secretion of glucagon-like peptide-1. PNAS Exenatide (Byetta R) and the GLP-1 analog Liraglutide. 104(38): 15069-74 and Parlevliet, et al., 2007, "Oxyntomodu Other drugs inhibit DPP-IV, an enzyme that rapidly degrades lin ameliorates glucose intolerance in mice fed a high-fat endogenous GLP-1. Exenatide is a GLP-1 receptor agonist diet.” Am J Physiol Endocrinol Metab 294(1):E142-7). Gua that is degraded more slowly by DPP-IV. Liraglutide, a nylin and uroguanylinare peptides of 15- and 16-amino acids GLP-1 analog, is attached to a fatty acid molecule that binds in length, respectively, that are reportedly secreted by intes to albumin and slows the rate of GLP-1 release and its deg tinal epithelial cells as prohormones and require enzymatic radation. (See, e.g., Nicolucci, et al., 2008, “Incretin-based conversion into active hormones. Recently, it has been therapies: a new potential treatment approach to overcome reported that uroguanylin may have a satiety-inducing func clinical inertia in type 2 diabetes.” Acta Biomedica 79(3): tion. (See Seeley & Tschop, 2011, “Uroguanylin: how the gut 184-91 and U.S. Pat. No. 5,424,286 “Exendin-3 and exen got another satiety hormone. J Clin Invest 121 (9):3384 din-4 polypeptides, and pharmaceutical compositions com 3386; Valentino et al., 2011, “A Uroguanylin-GUCY2C prising same.) Endocrine Axis Regulates Feeding in Mice. J Clin Invest 0004 Metformin is an antihyperglycemic agent which doe:10.1172/JCI57925.) improves glucose tolerance in patients with type II diabetes 0007. It has also been reported that there are taste receptor by lowering both basal and post-prandial plasma glucose. Its like elements present on the L-cells and K-cells in the intes pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin tine (Hofer, et al., 1996, “Taste receptor-like cells in the ratgut decreases hepatic glucose production, decreases intestinal identified by expression of alpha-gustducin’ Proc Natl Acad absorption of glucose, and improves insulin sensitivity by Sci USA 93:6631-6634). For example, the sweet taste recep increasing peripheral glucose uptake and utilization. How tors are heterodimers of the T1R2 and T1R3 GPCRs and have ever, metformin is reported to be substantially excreted by the been proposed to be identical to those sweet taste receptors kidney, and the risk of metformin accumulation and lactic found on taste buds. The umami receptors are reported to be acidosis increases with the degree of impairment of renal T1R1 and T1R3 heterodimers (Xu, et al., 2004, “Different function. For example, in patients with known or Suspected functional roles of T1R subunits in the heteromeric taste impaired renal function Such as those with advanced age, receptors.” Proc Natl AcadSci USA 101: 14258-14263 and metforminadministration requires close dose monitoring and titration to prevent lactic acidosis, a potentially fatal meta Sternini, et al., 2008, “Enteroendocrine cells: a site of taste bolic complication. Patients with concomitant cardiovascular in gastrointestinal chemosensing. Curr Opin Endocrinol or liver disease, sepsis, and hypoxia have also increased the Diabetes Obes 15: 73-78). Stimulation of taste or taste-like risk of lactic acidosis. Thus, metformin remains an unavail receptors by luminal nutrients has reportedly resulted in api able and/or risky treatment for certain patient groups due to its cal secretion of L-cell products such as GLP-1, PYY. oxyn side effects. tomodulin and glycentin, and K-cell products Such as GIP. 0005. Until very recently, obesity treatments include two and into the portal vein (Jang, et al., 2007, PNAS 104(38): FDA-approved drugs. Orlistat (Xenical(R) reduces intestinal 15069-74). In a glucose-dependent manner, GLP-1 and GIP fat absorption by inhibiting pancreatic lipase. Sibutramine reportedly increase insulin release from beta cells (an effect US 2015/0265555 A1 Sep. 24, 2015 known as the incretin effect). In addition, GLP-1 reportedly drome), delayed gastric emptying, dyslipidemia, post-pran inhibits glucagon release and gastric emptying. GLP-1, oxyn dial dyslipidemia, hyperlipidemia, hypertriglyceridemia, tomodulin and PYY 3-36 are considered to be satiety signals post hypertriglyceridemia, insulin resistance, bone loss dis (Strader, et al., 2005, "Gastrointestinal hormones and food orders, osteopenia, osteoporosis, muscle wasting disease, intake. Gastroenterology 128: 175-191). Receptors for fatty muscle degenerative disorders, polycystic ovary syndrome acids (e.g., GPR40 and/or GPR120) (Hirasawa, et al., 2005, (PCOS), non-alcoholic fatty liver disease (NAFL), non-alco Free fatty acids regulate gut incretin glucagon-like peptide-1 holic steatohepatitis (NASH), immune disorders of the gut secretion through GPR120, NatMed 11:90-94) and bile acids (e.g., celiac disease), bowel irregularity, irritable bowel syn (e.g., Gpbar1/M-Bar/TGRS) (Maruyama, et al., 2006. “Tar drome (IBS), inflammatory bowel disease (IBD), including, geted disruption of G protein-coupled bile acid receptor 1 e.g., ulcerative colitis, Crohn's disease, short bowel syn (Gpbar1/M-Bar) in mice.” J Endocrinol 191: 197-205 and drome and peripheral neuropathy (e.g., diabetic neuropathy).
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