Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists.
Jun ShiZhengxiang GuElizabeth Anne JuricaXimao WuLauren E HaqueKristin N WilliamsAndres S HernandezZhenqiu HongQi GaoMarta DabrosAkin H DavulcuArvind MathurRichard A RampullaArun Kumar GuptaRamya JayaramAtsu ApedoDouglas B MooreHeng LiuLori K KunselmanEdward J BradyJason J WilkesBradley A ZinkerHong CaiYue-Zhong ShuQin SunElizabeth A DierksKimberly A FosterCarrie XuTao WangReshma PanemangaloreMary Ellen CvijicChunshan XieGary G CaoMin ZhouJohn KrupinskiJean M WhaleyJeffrey A RoblWilliam R EwingBruce Alan EllsworthPublished in: Journal of medicinal chemistry (2018)
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.