Structure–Activity Relationship Study and Biological Evaluation of 2‑(Disubstituted phenyl)-indole-5-propanoic Acid Derivatives as GPR40 Full Agonists

G-protein-coupled receptor 40 (GPR40)
is considered as an attractive
drug target for treating type 2 diabetes, owing to its role in the
free fatty acid-mediated increase in glucose-stimulated insulin secretion
(GSIS) from pancreatic β-cells. To identify a new chemotype
of GPR40 agonist, a series of 2-aryl-substituted indole-5-propanoic
acid derivatives were designed and synthesized. We identified two
GPR40 agonist lead compounds4k (3-[2-(4-fluoro-2-methylphenyl)-1H-indol-5-yl]­propanoic acid) and 4o (3-[2-(2,5-dimethylphenyl)-1H-indol-5-yl]­propanoic acid), having GSIS and glucagon-like
peptide 1 secretory effects. Unlike previously reported GPR40 partial
agonists that only activate the Gq pathway, 4k and 4o activated both the Gq and Gs signaling pathways and were characterized as GPR40 full agonists.
In in vivo efficacy studies, 4o significantly
improved glycemic control in both C57BL/6J and db/db mice and increased
plasma-active GLP-1 in C57BL/6J mice. Thus, 4o represents
a promising lead for further development as a novel GPR40 full agonist
against type 2 diabetes.