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Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

ABSTRACT: 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.

SUBMITTER: Plummer CW

PROVIDER: S-EPMC5304298 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

Plummer Christopher W CW Clements Matthew J MJ Chen Helen H Rajagopalan Murali M Josien Hubert H Hagmann William K WK Miller Michael M Trujillo Maria E ME Kirkland Melissa M Kosinski Daniel D Mane Joel J Pachanski Michele M Cheewatrakoolpong Boonlert B Nolting Andrew F AF Orr Robert R Christensen Melodie M Campeau Louis-Charles LC Wright Michael J MJ Bugianesi Randal R Souza Sarah S Zhang Xiaoping X Di Salvo Jerry J Weinglass Adam B AB Tschirret-Guth Richard R Nargund Ravi R Howard Andrew D AD Colletti Steven L SL

ACS medicinal chemistry letters 20170123 2

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 opt ...[more]

PMID: 28197316

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Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

Publications

Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

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