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

Abstract

Dual PPARα/δ 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 PPARα/δ agonist compound 6 was identified with highly activities on PPARα/δ and higher selectivity against PPARγ than that of GFT505. The modeling study revealed that compound 6 binds well to the binding pockets of PPARα and PPARδ, which formed multiple hydrogen bonds with key residues related to the activation of PPARα and PPARδ. 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 PPARα/δ agonist.

Keywords: Dual agonist; GFT505; PPAR; Selectivity; T2DM.