Journal of Medicinal Chemistry p. 681 - 694 (2018)
Update date:2022-08-15
Topics:
Shi, Jun
Gu, Zhengxiang
Jurica, Elizabeth Anne
Wu, Ximao
Haque, Lauren E.
Williams, Kristin N.
Hernandez, Andres S.
Hong, Zhenqiu
Gao, Qi
Dabros, Marta
Davulcu, Akin H.
Mathur, Arvind
Rampulla, Richard A.
Gupta, Arun Kumar
Jayaram, Ramya
Apedo, Atsu
Moore, Douglas B.
Liu, Heng
Kunselman, Lori K.
Brady, Edward J.
Wilkes, Jason J.
Zinker, Bradley A.
Cai, Hong
Shu, Yue-Zhong
Sun, Qin
Dierks, Elizabeth A.
Foster, Kimberly A.
Xu, Carrie
Wang, Tao
Panemangalore, Reshma
Cvijic, Mary Ellen
Xie, Chunshan
Cao, Gary G.
Zhou, Min
Krupinski, John
Whaley, Jean M.
Robl, Jeffrey A.
Ewing, William R.
Ellsworth, Bruce Alan
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.
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