Novel 2-mercapto imidazole and triazole derivatives as potent TGR5 receptor agonists

Obesity and overweight, from World Health Organization, http://www.who.int/mediacentre/factsheets/fs311/en/, (June 2016). De Fronzo, 2009, From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus, Diabetes, 58, 773, 10.2337/db09-9028 Ashiya, 2007, Non-insulin therapies for type 2 diabetes, Nat Rev Drug Discov, 6, 777, 10.1038/nrd2420 American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014; 37(suppl 1): S14–S80 Erratum in: Diabetes Care. 2014; 37: 887. Li, 2014, Bile acid signaling in metabolic disease and drug therapy, Pharmacol Rev, 66, 948, 10.1124/pr.113.008201 Thomas, 2008, Nat Rev Drug Disc, 7, 678, 10.1038/nrd2619 Tiwari, 2009, TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders, Drug Discov Today, 14, 523, 10.1016/j.drudis.2009.02.005 Thomas, 2009, TGR5-mediated bile acid sensing controls glucose homeostasis, Cell Metab, 10, 167, 10.1016/j.cmet.2009.08.001 Watanabe, 2006, Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation, Nature, 439, 484, 10.1038/nature04330 Pols, 2011, TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading, Cell Metab, 14, 747, 10.1016/j.cmet.2011.11.006 Xu, 2016, Recent progress on bile acid receptor modulators for treatment of metabolic diseases, J Med Chem, 59, 6553, 10.1021/acs.jmedchem.5b00342 Zhong, 2010, TGR5 as a therapeutic target for treating obesity, Curr Top Med Chem, 10, 386, 10.2174/156802610790980576 Pellicciari, 2009, Discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity, J Med Chem, 52, 7958, 10.1021/jm901390p Futatsugi, 2013, Optimization of triazole-based TGR5 agonists towards orally available agents, Med Chem Commun, 4, 205, 10.1039/C2MD20174G Chen, 2018, J Med Chem, 61, 7589, 10.1021/acs.jmedchem.8b00308 Agarwal, 2016, ACS Med Chem Lett, 7, 1134, 10.1021/acsmedchemlett.6b00331 Agarwal, 2016, ACS Med Chem Lett, 7, 51, 10.1021/acsmedchemlett.5b00323 Agarwal, 2018, Evaluation of novel TGR5 agonist in combination with Sitagliptin for possible treatment of type 2 diabetes, Bioorg Med Chem Lett, 28, 1849, 10.1016/j.bmcl.2018.04.011 Agarwal, 2012, Silica-gel catalyzed facile synthesis of 3,4-dihydropyrimidinones, Bull Korean Chem Soc, 33, 377, 10.5012/bkcs.2012.33.2.377 S. Agarwal, M.R. Jain, P.R. Patel, 2-Thio-imidazole derivatives as TGR5 modulators. PCT Int. Appl. WO 2013/054338, 18 April 2013 (Appl. PCT/IN2012/000471, 4.07.2012). Agarwal, 2014, Indian Pat. Appl. Waring, 2015, An analysis of the attrition of drug candidates from four major pharmaceutical companies, Nat Rev Drug Discov, 14, 475, 10.1038/nrd4609