Phillips, Dean, Gao, Wenqi, Yang, Yang, Zhang, Guobao, Lerario, Isabelle, Lau, Thomas, Jiang, Jiqing, Wang, Xia, Nguyen, Deborah, Bhat, Barkur, Trotter, Carol, Welzel, Gustav, Sullivan, Heather, Landry, Jannine, Chen, Yali, Joseph, Sean, Li, Chun, Gordon, William, Richmond, Wendy, Johnson, Kevin, Bretz, Angela, Bursulaya, Badry, Pan, Shifeng, Mcnamara, Peter and Seidel, Martin (2014) Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: Structure-activity relationships, lead optimization, and chronic in vivo efficacy. Journal of Medicinal Chemistry, 57 (8). pp. 3263-3282. ISSN 1520-4804

Abstract

Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing. © 2014 American Chemical Society.

Item Type:	Article
Date Deposited:	14 Mar 2018 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/11243