Design and Synthesis of Novel, Selective GPR40 AgoPAMs

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2017 Feb 16

PMID 28197316

Citations 7

Authors

Christopher W Plummer

Matthew J Clements

Helen Chen

Murali Rajagopalan

Hubert Josien

William K Hagmann

Michael Miller

Maria E Trujillo

Melissa Kirkland

Daniel Kosinski

Joel Mane

Michele Pachanski

Boonlert Cheewatrakoolpong

Andrew F Nolting

Robert Orr

Melodie Christensen

Louis-Charles Campeau

Michael J Wright

Randal Bugianesi

Sarah Souza

Xiaoping Zhang

Jerry Di Salvo

Adam B Weinglass

Richard Tschirret-Guth

Ravi Nargund

Andrew D Howard

Steven L Colletti

Affiliations

Soon will be listed here.

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 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

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