Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2016 Dec 21

PMID 27994747

Citations 4

Authors

Liangqin Guo

Dann L Parker

Yi Zang

Ramzi F Sweis

Weiguo Liu

Edward C Sherer

Nicole Buist

Jenna Terebetski

Terri Kelly

Randal Bugianesi

Birgit T Priest

Karen H Dingley

Xiaofang Li

Stan Mitelman

Gino Salituro

Maria E Trujillo

Michele Pachanski

Melissa Kirkland

Mary Ann Powles

George J Eiermann

Yue Feng

Jin Shang

Andrew D Howard

Feroze Ujjainwalla

Christopher J Sinz

John S Debenham

Scott D Edmondson

Ravi P Nargund

William K Hagmann

Derun Li

Affiliations

Soon will be listed here.

Abstract

GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound , which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.

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