AMG 837: a potent, orally bioavailable GPR40 agonist

  • Bioorg Med Chem Lett. 2012 Jan 15;22(2):1267-70. doi: 10.1016/j.bmcl.2011.10.118.
Jonathan B Houze  1 ,  Liusheng Zhu ,  Ying Sun ,  Michelle Akerman ,  Wei Qiu ,  Alex J Zhang ,  Rajiv Sharma ,  Michael Schmitt ,  Yingcai Wang ,  Jiwen Liu ,  Jinqian Liu ,  Julio C Medina ,  Jeff D Reagan ,  Jian Luo ,  George Tonn ,  Jane Zhang ,  Jenny Ying-Lin Lu ,  Michael Chen ,  Edwin Lopez ,  Kathy Nguyen ,  Li Yang ,  Liang Tang ,  Hui Tian ,  Steven J Shuttleworth ,  Daniel C-H Lin
Affiliations
  • 1. Amgen Inc. 1120 Veterans Blvd., South San Francisco, CA 94080, USA. [email protected]
PMID: 22217876 DOI: 10.1016/j.bmcl.2011.10.118
Abstract

The discovery that certain long chain Fatty Acids potentiate glucose stimulated Insulin secretion through the previously Orphan Receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of Insulin secretion in rodents.

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