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

摘要

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 beta-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.