Discovery of Novel G‐Protein‐Coupled Receptor 40 Agonist with Phenylacetic Acid Scaffold for the Treatment of Type 2 Diabetes

Abstract

The G‐protein‐coupled receptor 40 (GPR40) plays an important role in glucose‐stimulated insulin secretion and therefore may be a promising anti‐diabetic target. In this study, we have replaced the phenylpropionic acid of GPR40 agonist GW9508 with phenylacetic acid to avoid β‐oxidation. The molecular modeling study based on phenylacetic acid scaffold suggested that the present series fitted very well with the binding pocket of GPR40. Further structure‐activity relationship study provided the optimal compound 6, which revealed better in vivo hypoglycemic effect than GW9508 both in normal and type 2 diabetic mice. These findings suggested that compound 6 was meaningful for further investigation and highlighted its potential as a lead compound.

Mechanisms of drugs in the treatment of type 2 diabetes mellitus

“…GPR40 agonists rarely lead to the risk of hypoglycemia and demonstrate fewer side effects. GPR40 agonists are proven to assist in controlling food intake, reducing fatty tissues, and beta-cell apoptosis [10,11] . GPR40 agonists show great potential even in the early stages of development.…”

“…GPR40 agonists are proven to assist in controlling food intake, reducing fatty tissues, and beta-cell apoptosis. [ 10 , 11 ] GPR40 agonists show great potential even in the early stages of development. However, GPR40 agonists are still in the early stage of development.…”