Design, synthesis, and biological evaluation of novel dual PPARα/δ agonists for the treatment of T2DM

Dual PPAR alpha/delta agonists have been considered as potential therapeutics for the treatment of type 2 diabetes mellitus. After comprehensive structure-activity relationship study based on GFT505, a novel dual PPAR alpha/delta agonist compound 6 was identified with highly activities on PPAR alpha/8 and higher selectivity against PPAR gamma than that of GFT505. The modeling study revealed that compound 6 binds well to the binding pockets of PPAR alpha and PPAR delta, which formed multiple hydrogen bonds with key residues related to the activation of PPAR alpha and PPAR delta. Moreover, oral glucose tolerance test exhibited that compound 6 exerts dose-dependent anti-diabetic effects in ob/ob mice and reveals similar potency to that of GFT505, the most advanced candidate in this field. These findings suggested that compound 6 is a promising candidate for further researches, and the extended chemical space might help us to explore better PPAR alpha/delta agonist.