Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs

被引：8

作者：

Chen, Helen Y. ^{[1
]}

Plummer, Christopher W. ^{[1
]}

Xiao, Dong ^{[1
]}

Chobanian, Harry R. ^{[1
,3
]}

DeMong, Duane ^{[1
]}

Miller, Michael ^{[1
]}

Trujillo, Maria E. ^{[4
]}

Kirkland, Melissa ^{[4
]}

Kosinski, Daniel ^{[4
]}

Mane, Joel ^{[4
]}

Pachanski, Michele ^{[4
]}

Cheewatrakoolpong, Boonlert ^{[4
]}

Di Salvo, Jerry ^{[5
]}

Thomas-Fowlkes, Brande ^{[5
]}

Souza, Sarah ^{[5
]}

Tatosian, Daniel A. ^{[3
]}

Chen, Qing ^{[3
]}

Hafey, Michael J. ^{[3
]}

Houle, Robert ^{[3
]}

Nolting, Andrew F. ^{[2
]}

Orr, Robert ^{[2
]}

Ehrhart, Juliann ^{[4
]}

Weinglass, Adam B. ^{[5
]}

Tschirret-Guth, Richard ^{[3
]}

Howard, Andrew D. ^{[4
]}

Colletti, Steven L. ^{[1
]}

机构：

[1] Merck & Co Inc, Dept Discovery Chem, Kenilworth, NJ 07033 USA

[2] Merck & Co Inc, Dept Proc Chem, Kenilworth, NJ 07033 USA

[3] Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Kenilworth, NJ 07033 USA

[4] Merck & Co Inc, Dept In Vivo Pharmacol, Kenilworth, NJ 07033 USA

[5] Merck & Co Inc, Dept In Vitro Pharmacol, Kenilworth, NJ 07033 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 07期

关键词：

GPR40; FFA1; GPCR; diabetes; insulin secretagogue; AgoPAM; chroman; INDUCED LIVER-INJURY; POTENT; DISCOVERY; INHIBITION; CELLS; ACIDS;

D O I：

10.1021/acsmedchemlett.8b00149

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

引用

页码：685 / 690

页数：11

共 21 条

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