Design, synthesis, and biological evaluation of imidazolidinone derivatives as potent PPARα/δ agonists for the treatment of cholestatic liver diseases

Cholestatic liver disease (CLD) represents a significant and growing public health concern, and there is a lack of effective therapeutic drug in clinical practice. Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for CLD. In this study, a series of novel imidazolidinone PPARα/δ agonists were developed, and the preferred compound 8 displayed potent and well-balanced agonistic activity. Compound 8 showed high selectivity over other related nuclear receptors and effectively regulated the PPARα/δ target genes expression in mice. Notably, compound 8 demonstrated good pharmacokinetic profiles and potent in vivo anti-CLD effects. Collectively, compound 8 holds promise for developing an anti-CLD agent.