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Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists. 2018
Jun Shi, and
Zhengxiang Gu, and
Elizabeth Anne Jurica, and
Ximao Wu, and
Lauren E Haque, and
Kristin N Williams, and
Andres S Hernandez, and
Zhenqiu Hong, and
Qi Gao, and
Marta Dabros, and
Akin H Davulcu, and
Arvind Mathur, and
Richard A Rampulla, and
Arun Kumar Gupta, and
Ramya Jayaram, and
Atsu Apedo, and
Douglas B Moore, and
Heng Liu, and
Lori K Kunselman, and
Edward J Brady, and
Jason J Wilkes, and
Bradley A Zinker, and
Hong Cai, and
Yue-Zhong Shu, and
Qin Sun, and
Elizabeth A Dierks, and
Kimberly A Foster, and
Carrie Xu, and
Tao Wang, and
Reshma Panemangalore, and
Mary Ellen Cvijic, and
Chunshan Xie, and
Gary G Cao, and
Min Zhou, and
John Krupinski, and
Jean M Whaley, and
Jeffrey A Robl, and
William R Ewing, and
Bruce Alan Ellsworth
Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
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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Jun Shi, and
Zhengxiang Gu, and
Elizabeth Anne Jurica, and
Ximao Wu, and
Lauren E Haque, and
Kristin N Williams, and
Andres S Hernandez, and
Zhenqiu Hong, and
Qi Gao, and
Marta Dabros, and
Akin H Davulcu, and
Arvind Mathur, and
Richard A Rampulla, and
Arun Kumar Gupta, and
Ramya Jayaram, and
Atsu Apedo, and
Douglas B Moore, and
Heng Liu, and
Lori K Kunselman, and
Edward J Brady, and
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Qin Sun, and
Elizabeth A Dierks, and
Kimberly A Foster, and
Carrie Xu, and
Tao Wang, and
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Chunshan Xie, and
Gary G Cao, and
Min Zhou, and
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Jean M Whaley, and
Jeffrey A Robl, and
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Bruce Alan Ellsworth
May 2013,
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Elizabeth Anne Jurica, and
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Kristin N Williams, and
Andres S Hernandez, and
Zhenqiu Hong, and
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Marta Dabros, and
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Arun Kumar Gupta, and
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Atsu Apedo, and
Douglas B Moore, and
Heng Liu, and
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Jason J Wilkes, and
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Kimberly A Foster, and
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Min Zhou, and
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Jean M Whaley, and
Jeffrey A Robl, and
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Bruce Alan Ellsworth
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Qi Gao, and
Marta Dabros, and
Akin H Davulcu, and
Arvind Mathur, and
Richard A Rampulla, and
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Ramya Jayaram, and
Atsu Apedo, and
Douglas B Moore, and
Heng Liu, and
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Edward J Brady, and
Jason J Wilkes, and
Bradley A Zinker, and
Hong Cai, and
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Jean M Whaley, and
Jeffrey A Robl, and
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Jeffrey A Robl, and
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Jeffrey A Robl, and
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