Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure鈥揂ctivity Relationships, Lead Optimization, and Chronic In Vivo Eff

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• 作者：Dean P. Phillips ; Wenqi Gao ; Yang Yang ; Guobao Zhang ; Isabelle K. Lerario ; Thomas L. Lau ; Jiqing Jiang ; Xia Wang ; Deborah G. Nguyen ; B. Ganesh Bhat ; Carol Trotter ; Heather Sullivan ; Gustav Welzel ; Jannine Landry ; Yali Chen ; Sean B. Joseph ; Chun Li ; W. Perry Gordon ; Wendy Richmond ; Kevin Johnson ; Angela Bretz ; Badry Bursulaya ; Shifeng Pan ; Peter McNamara ; H. Martin Seidel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3263-3282
• 全文大小：751K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

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.