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Optimization of GPR40 Agonists for Type 2 Diabetes.

ABSTRACT: GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration.

SUBMITTER: Liu JJ

PROVIDER: S-EPMC4027784 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Optimization of GPR40 Agonists for Type 2 Diabetes.

Liu Jiwen Jim JJ Wang Yingcai Y Ma Zhihua Z Schmitt Mike M Zhu Liusheng L Brown Sean P SP Dransfield Paul J PJ Sun Ying Y Sharma Rajiv R Guo Qi Q Zhuang Run R Zhang Jane J Luo Jian J Tonn George R GR Wong Simon S Swaminath Gayathri G Medina Julio C JC Lin Daniel C-H DC Houze Jonathan B JB

ACS medicinal chemistry letters 20140206 5

GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These effo ...[more]

PMID: 24900872

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