Discovery of the First Subnanomolar PPAR/ Dual Agonist for the Treatment of Cholestatic Liver Diseases

Peroxisomeproliferator-activator receptors alpha/delta (PPAR alpha/delta)are considered as potential drug targets for cholestatic liver diseases(CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis.In this work, we developed a series of hydantoin derivatives as potentPPAR alpha/delta dual agonists. Representative compound V1 exhibited PPAR alpha/delta dual agonistic activity at the subnanomolarlevel (PPAR alpha EC50 = 0.7 nM; PPAR delta EC50 = 0.4 nM) and showed excellent selectivity over other related nuclearreceptors. The crystal structure revealed the binding mode of V1 and PPAR delta at 2.1 angstrom resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) propertiesand a good safety profile. Notably, V1 showed potentanti-CLD and antifibrotic effects in preclinical models at very lowdoses (0.03 and 0.1 mg/kg). Collectively, this work provides a promisingdrug candidate for treating CLD and other hepatic fibrosis diseases.