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. (C) 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.