1区 · 医学
Article
作者: Whaley, Jean M. ; Robl, Jeffrey A. ; Xu, Carrie ; Liu, Heng ; Moore, Douglas B. ; Apedo, Atsu ; Panemangalore, Reshma ; Shi, Jun ; Dierks, Elizabeth A. ; Gao, Qi ; Ellsworth, Bruce Alan ; Jayaram, Ramya ; Hernandez, Andres S. ; Wilkes, Jason J. ; Williams, Kristin N. ; Xie, Chunshan ; Shu, Yue-Zhong ; Gupta, Arun Kumar ; Kunselman, Lori K. ; Wang, Tao ; Mathur, Arvind ; Cao, Gary G. ; Hong, Zhenqiu ; Brady, Edward J. ; Gu, Zhengxiang ; Ewing, William R. ; Wu, Ximao ; Sun, Qin ; Zhou, Min ; Krupinski, John ; Jurica, Elizabeth Anne ; Davulcu, Akin H. ; Cvijic, Mary Ellen ; Cai, Hong ; Foster, Kimberly A. ; Zinker, Bradley A. ; Haque, Lauren E. ; Dabros, Marta ; Rampulla, Richard A.
G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
