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

ABSTRACT: 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.

SUBMITTER: Chen HY

PROVIDER: S-EPMC6047031 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Chen Helen Y HY Plummer Christopher W CW Xiao Dong D Chobanian Harry R HR DeMong Duane D Miller Michael M Trujillo Maria E ME Kirkland Melissa M Kosinski Daniel D Mane Joel J Pachanski Michele M Cheewatrakoolpong Boonlert B Di Salvo Jerry J Thomas-Fowlkes Brande B Souza Sarah S Tatosian Daniel A DA Chen Qing Q Hafey Michael J MJ Houle Robert R Nolting Andrew F AF Orr Robert R Ehrhart Juliann J Weinglass Adam B AB Tschirret-Guth Richard R Howard Andrew D AD Colletti Steven L SL

ACS medicinal chemistry letters 20180614 7

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 <i>AP5</i>, which possesses an improved metabolic profile while demonstrating sustained glucose lowering. ...[more]

PMID: 30034601

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