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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

Phillips, Dean and Gao, Wenqi and Yang, Yang and Zhang, Guobao and Lerario, Isabelle and Lau, Thomas and Jiang, Jiqing and Wang, Xia and Nguyen, Deborah and Bhat, Barkur and Trotter, Carol and Welzel, Gustav and Sullivan, Heather and Landry, Jannine and Chen, Yali and Joseph, Sean and Li, Chun and Gordon, William and Richmond, Wendy and Johnson, Kevin and Bretz, Angela and Bursulaya, Badry and Pan, Shifeng and 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

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