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ACS Med Chem Lett. 2017 Jan 23;8(2):221-226. doi: 10.1021/acsmedchemlett.6b00443. eCollection 2017 Feb 9.

Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

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Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.


GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.


FFA1; GPCR; GPR40; agoPAM; chroman; diabetes; insulin secretogogue

Conflict of interest statement

The authors declare no competing financial interest.

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