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

  • ACS Med Chem Lett. 2018 Jun 14;9(7):685-690. doi: 10.1021/acsmedchemlett.8b00149.
Helen Y Chen  1 ,  Christopher W Plummer  1 ,  Dong Xiao  1 ,  Harry R Chobanian  1 ,  Duane DeMong  1 ,  Michael Miller  1 ,  Maria E Trujillo  1 ,  Melissa Kirkland  1 ,  Daniel Kosinski  1 ,  Joel Mane  1 ,  Michele Pachanski  1 ,  Boonlert Cheewatrakoolpong  1 ,  Jerry Di Salvo  1 ,  Brande Thomas-Fowlkes  1 ,  Sarah Souza  1 ,  Daniel A Tatosian  1 ,  Qing Chen  1 ,  Michael J Hafey  1 ,  Robert Houle  1 ,  Andrew F Nolting  1 ,  Robert Orr  1 ,  Juliann Ehrhart  1 ,  Adam B Weinglass  1 ,  Richard Tschirret-Guth  1 ,  Andrew D Howard  1 ,  Steven L Colletti  1
Affiliations
  • 1. Departments of Discovery Chemistry, Process Chemistry, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, In Vivo Pharmacology, and In Vitro Pharmacology, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
PMID: 30034601 DOI: 10.1021/acsmedchemlett.8b00149
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.

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