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Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
Jun Shi1, Zhengxiang Gu1, Elizabeth Anne Jurica1
1Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
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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