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

作者：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

来源：Journal of Medicinal Chemistry, 2014, 57(8): 3263-3282.

DOI：10.1021/jm401731q

• BILE-ACID RECEPTOR
• PEPTIDASE-IV INHIBITOR
• STIMULATION
• ACTIVATION
• SNAPSHOT
• DESIGN
• PK

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.

• 出版日期2014-4-24