1区 · 医学
Article
作者: Krupinski, John ; Shu, Yue-Zhong ; Jayaram, Ramya ; Hong, Zhenqiu ; Zhou, Min ; Ellsworth, Bruce Alan ; Cao, Gary G. ; Ewing, William R. ; Hernandez, Andres S. ; Panemangalore, Reshma ; Dierks, Elizabeth A. ; Rampulla, Richard A. ; Dabros, Marta ; Kunselman, Lori K. ; Liu, Heng ; Xie, Chunshan ; Zinker, Bradley A. ; Gupta, Arun Kumar ; Williams, Kristin N. ; Wang, Tao ; Gu, Zhengxiang ; Apedo, Atsu ; Xu, Carrie ; Moore, Douglas B. ; Wu, Ximao ; Shi, Jun ; Wilkes, Jason J. ; Jurica, Elizabeth Anne ; Cai, Hong ; Cvijic, Mary Ellen ; Mathur, Arvind ; Gao, Qi ; Foster, Kimberly A. ; Davulcu, Akin H. ; Sun, Qin ; Whaley, Jean M. ; Haque, Lauren E. ; Robl, Jeffrey A. ; Brady, Edward J.
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.
