Compound 16a, a novel arylimidazole derivative, exhibited potent PPARδ agonistic activity (EC50 = 0.50 nM) and showed dose-dependent antirenal fibrosis effects in a mouse model.
Does compound 16a exhibit PPARδ agonistic activity and antirenal fibrosis effects in a mouse model of unilateral ureteral obstruction?
Compound 16a is a potent, selective PPARδ agonist that demonstrates antirenal fibrosis effects in a mouse model by restoring fatty acid oxidation.
Effect estimate: EC50 = 0.50 nM
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.
Zheng et al. (Tue,) conducted a other in Renal fibrosis. Compound 16a (arylimidazole derivative) was evaluated on PPARδ agonistic activity and antirenal fibrosis effects (EC50 = 0.50 nM). Compound 16a, a novel arylimidazole derivative, exhibited potent PPARδ agonistic activity (EC50 = 0.50 nM) and showed dose-dependent antirenal fibrosis effects in a mouse model.