Design, Synthesis, and Biological Evaluation of Arylimidazole Derivatives as Potent PPARδ Agonists for the Treatment of Renal Fibrosis.

Peroxisome proliferator-activator receptor δ (PPARδ) is ubiquitously expressed in the kidney, and its agonists are increasingly being recognized as a potential therapeutic strategy for renal diseases. In this work, we developed a series of arylimidazole derivatives as potent PPARδ agonists. Among them, compound 16a exhibited potent PPARδ agonistic activity (EC50 = 0.50 nM) and high selectivity over PPARα/γ and some other nuclear receptors. The X-ray cocrystal structure revealed the binding mode of 16a and PPARδ at 1.94 Å resolution. Remarkably, compound 16a exhibited acceptable pharmacokinetic properties and good safety profiles in vivo and showed antirenal fibrosis effects in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Mechanistically, 16a activated PPARδ to restore fatty acid oxidation to attenuate TGF-β1-induced renal fibroblast activation. Collectively, 16a warrants further investigation as a promising drug candidate for treating renal fibrosis.