2. Academic Validation
  3. Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

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

Affiliation

  • 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.

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