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

  • J Med Chem. 2023 Jun 8;66(11):7331-7354. doi: 10.1021/acs.jmedchem.2c02123.
Zhiqi Feng  1 ,  Jiehao Xiang  1 ,  Gang Sun  1 ,  Hui Liu  1 ,  Yanyan Wang  1 ,  Xin Liu  1 ,  Jin Feng  1 ,  Qinglong Xu  1 ,  Xiaoan Wen  1 ,  Haoliang Yuan  1 ,  Hongbin Sun  1  2 ,  Liang Dai  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
PMID: 37243609 DOI: 10.1021/acs.jmedchem.2c02123
Abstract

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 EC50 = 0.7 nM; PPARδ EC50 = 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.

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