Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

  • J Med Chem. 2018 Feb 8;61(3):681-694. doi: 10.1021/acs.jmedchem.7b00982.
Jun Shi  1 ,  Zhengxiang Gu  1 ,  Elizabeth Anne Jurica  1 ,  Ximao Wu  1 ,  Lauren E Haque  1 ,  Kristin N Williams  1 ,  Andres S Hernandez  1 ,  Zhenqiu Hong  1 ,  Qi Gao  1 ,  Marta Dabros  1 ,  Akin H Davulcu  1 ,  Arvind Mathur  1 ,  Richard A Rampulla  1 ,  Arun Kumar Gupta  1 ,  Ramya Jayaram  1 ,  Atsu Apedo  1 ,  Douglas B Moore  1 ,  Heng Liu  1 ,  Lori K Kunselman  1 ,  Edward J Brady  1 ,  Jason J Wilkes  1 ,  Bradley A Zinker  1 ,  Hong Cai  1 ,  Yue-Zhong Shu  1 ,  Qin Sun  1 ,  Elizabeth A Dierks  1 ,  Kimberly A Foster  1 ,  Carrie Xu  1 ,  Tao Wang  1 ,  Reshma Panemangalore  1 ,  Mary Ellen Cvijic  1 ,  Chunshan Xie  1 ,  Gary G Cao  1 ,  Min Zhou  1 ,  John Krupinski  1 ,  Jean M Whaley  1 ,  Jeffrey A Robl  1 ,  William R Ewing  1 ,  Bruce Alan Ellsworth  1
Affiliations
  • 1. Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
PMID: 29316397 DOI: 10.1021/acs.jmedchem.7b00982
Abstract

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.

Products