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

作者：Zhiqi Feng, Jiehao Xiang, Gang Sun, Hui Liu, Yanyan Wang, Xin Liu, Jin Feng, Qing‐Long Xu, Xiaoan Wen, Haoliang Yuan, Hongbin Sun, Liang Dai · 发表于：Journal of Medicinal Chemistry · 年份：2023 · DOI：10.1021/acs.jmedchem.2c02123 · 被引用次数：17 · 研究领域：Drug Transport and Resistance Mechanisms、Liver Disease Diagnosis and Treatment、Peroxisome Proliferator-Activated Receptors

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) 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 potent PPARα/δ dual agonists. Representative compound V1 exhibited PPARα/δ dual agonistic activity at the subnanomolar level (PPARα EC 50 = 0.7 nM; PPARδ EC 50 = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARδ at 2.1 Å resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases.