1595144-42-5Relevant articles and documents
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 P.,Gao, Wenqi,Yang, Yang,Zhang, Guobao,Lerario, Isabelle K.,Lau, Thomas L.,Jiang, Jiqing,Wang, Xia,Nguyen, Deborah G.,Bhat, B. Ganesh,Trotter, Carol,Sullivan, Heather,Welzel, Gustav,Landry, Jannine,Chen, Yali,Joseph, Sean B.,Li, Chun,Gordon, W. Perry,Richmond, Wendy,Johnson, Kevin,Bretz, Angela,Bursulaya, Badry,Pan, Shifeng,McNamara, Peter,Seidel, H. Martin
, p. 3263 - 3282 (2014/05/20)
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.
