Synthesis and biological evaluation of 3-aryl-3-(4-phenoxy)-propionic acid as a novel series of G protein-coupled receptor 40 (GPR40) agonists

MEDI 59

Fengbin Song1, Songfeng Lu1, Joe Gunnet2, Jun Z. Xu1, Pam Wines1, Yin Liang1, Chris Baumann1, Jim Lenhard1, William V. Murray1, Keith T. Demarest1, and Gee-Hong Kuo1. (1) Drug Discovery Division, Johnson and Johnson Pharmaceutical Research and Development, L.L.C, 8 Clarke Dr, Cranbury, NJ 08512, (2) Chromocell Corporation, 675 U.S. Highway One, New Brunswick, NJ 08902
A high-throughput screening of J&J sub-libraries that contains carboxylic acid functional group resulted in the discovery of a bromophenyl derivative as a moderate potent GPR40 agonist. The chemical elaboration of this bromophenyl led to the discovery of a novel series of GPR40 agonists with submicromolar potency. Some of our compounds behaved as full-agonists when comparing its activities in increasing Ca+2 in HEK-293 cells to the endogenous ligand linoleic acid. Several GPR40 agonists have also been demonstrated to induce glucose-mediated insulin secretion in the mouse MIN6 cells. Our data may support the hypothesis that GPR40 may play an important role in FAs induced glucose-sensitive insulin secretion.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007