Discovery of first-in-class thiazole-based dual FFA1/PPAR delta agonists as potential anti-diabetic agents

摘要

The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor delta (PPAR delta) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPAR delta agonists would increase insulin secretion and sensibility by FFA1 and PPAR delta activation. In this study, we hybrid FFA1 agonist AM-4668 with PPAR delta agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPAR delta. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPAR delta agonist could be a valuable therapy for type 2 diabetes. (C) 2018 Elsevier Masson SAS. All rights reserved.