Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
Jun Shi* 
, Zhengxiang Gu, Elizabeth Anne Jurica , Ximao Wu, Lauren E. Haque, Kristin N. Williams, Andres S. Hernandez, Zhenqiu Hong, Qi Gao, Marta Dabros, Akin H. Davulcu, Arvind Mathur, Richard A. Rampulla, Arun Kumar Gupta, Ramya Jayaram, Atsu Apedo, Douglas B. Moore, Heng Liu, Lori K. Kunselman, Edward J. Brady, Jason J. Wilkes, Bradley A. Zinker, Hong Cai, Yue-Zhong Shu, Qin Sun, Elizabeth A. Dierks, Kimberly A. Foster, Carrie Xu, Tao Wang, Reshma Panemangalore, Mary Ellen Cvijic, Chunshan Xie, Gary G. Cao, Min Zhou, John Krupinski, Jean M. Whaley, Jeffrey A. Robl, William R. Ewing, and Bruce Alan Ellsworth
, Zhengxiang Gu, Elizabeth Anne Jurica , Ximao Wu, Lauren E. Haque, Kristin N. Williams, Andres S. Hernandez, Zhenqiu Hong, Qi Gao, Marta Dabros, Akin H. Davulcu, Arvind Mathur, Richard A. Rampulla, Arun Kumar Gupta, Ramya Jayaram, Atsu Apedo, Douglas B. Moore, Heng Liu, Lori K. Kunselman, Edward J. Brady, Jason J. Wilkes, Bradley A. Zinker, Hong Cai, Yue-Zhong Shu, Qin Sun, Elizabeth A. Dierks, Kimberly A. Foster, Carrie Xu, Tao Wang, Reshma Panemangalore, Mary Ellen Cvijic, Chunshan Xie, Gary G. Cao, Min Zhou, John Krupinski, Jean M. Whaley, Jeffrey A. Robl, William R. Ewing, and Bruce Alan Ellsworth
Research and Development, Bristol-Myers Squibb Co., P.O. Box 4000, Princeton, New Jersey 08540-4000, United States
J. Med. Chem., 2018, 61 (3), pp 681–694
DOI: 10.1021/acs.jmedchem.7b00982
Publication Date (Web): January 9, 2018
Copyright © 2018 American Chemical Society
*Phone: +1-609-466-5075. E-mail: jun.shi@bms.com.
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.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00982. Full crystallographic data for compound 8 have been deposited to the Cambridge Crystallographic Data Center (CCDC reference no. 1559162) and can be obtained free of charge via the Internet at http://www.ccdc.cam.ac.uk.
- Experimental procedures for the synthesis of compounds 3b–35 and methods for in vitro and in vivo biological studies (PDF)
- X-ray crystallographic data for 8 (CIF)
- Molecular formula strings (CSV)
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