| Autor: |
Gary G. Cao, Min Zhou, Ramya Jayaram, Douglas B. Moore, Andres S. Hernandez, Tao Wang, Jean M. Whaley, Yue-Zhong Shu, Carrie Xu, Lori Kunselman, Atsu Apedo, William R. Ewing, Reshma Panemangalore, Qi Gao, Arvind Mathur, Richard Rampulla, Bradley A. Zinker, Lauren Haque, Mary Ellen Cvijic, Marta Dabros, Arun Kumar Gupta, Heng Liu, Jeffrey A. Robl, Bruce A. Ellsworth, Jun Shi, Zhengxiang Gu, Jason J. Wilkes, Akin H. Davulcu, Kristin N. Williams, Elizabeth A. Dierks, John Krupinski, Zhenqiu Hong, Edward J. Brady, Ximao Wu, Qin Sun, Hong Cai, Chunshan Xie, Elizabeth A. Jurica, Kimberly A. Foster |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 61(3) |
| ISSN: |
1520-4804 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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