Design, synthesis and evaluation of potent G-protein coupled receptor 40 agonists

GPR40 has emerged as an attractive drug target for the treatment of type 2 diabetes due to its role in the enhancement of insulin secretion with glucose dependency. With the aim to improve the metabolic and safety profiles, a series of novel phenylpropionic acid derivatives were synthesized. Extensive structural optimization led to identification of compounds 22g and 23e as potent GPR40 agonists with moderate liver microsomal stability. All the discovery supported further exploration surrounding this scaffold.

Graphical abstractIn order to find a novel GPR40 agonist with improved metabolic and safety profiles, a series of novel phenylpropanoic acid derivatives were synthesized and evaluated for their agonistic activity on GPR40. SAR study and structural modification led to identification of compounds 22g and 23e as potent GPR40 agonists with moderate liver microsomal stability.Figure optionsDownload full-size imageDownload as PowerPoint slide