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Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-27 00:00:00 , 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-27 00:00:00 , 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
Affiliation
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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.
中文翻译：
发现有效和口服生物可用的二氢吡唑GPR40激动剂
G蛋白偶联受体40（GPR40）已成为治疗糖尿病的引人注目的靶标，因为临床上已证明它可以促进葡萄糖刺激的胰岛素分泌。在这里，我们报告了我们的努力，以开发具有双重作用机制的高选择性和有效的GPR40激动剂，该激动剂既可以促进葡萄糖依赖性胰岛素的分泌，又可以促进肠降血糖素的分泌。我们采用增加极性和化学型sp 3 / sp 2特征比率的策略，鉴定了BMS-986118（化合物4），该化合物在体外表现出强效和选择性的GPR40激动剂活性。体内化合物4 证明了促胰岛素功效和GLP-1分泌作用可改善急性动物模型中的葡萄糖控制。
更新日期：2018-01-27
中文翻译：
发现有效和口服生物可用的二氢吡唑GPR40激动剂
G蛋白偶联受体40（GPR40）已成为治疗糖尿病的引人注目的靶标，因为临床上已证明它可以促进葡萄糖刺激的胰岛素分泌。在这里，我们报告了我们的努力，以开发具有双重作用机制的高选择性和有效的GPR40激动剂，该激动剂既可以促进葡萄糖依赖性胰岛素的分泌，又可以促进肠降血糖素的分泌。我们采用增加极性和化学型sp 3 / sp 2特征比率的策略，鉴定了BMS-986118（化合物4），该化合物在体外表现出强效和选择性的GPR40激动剂活性。体内化合物4 证明了促胰岛素功效和GLP-1分泌作用可改善急性动物模型中的葡萄糖控制。
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