Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

  • J Med Chem. 2022 Feb 10;65(3):2571-2592. doi: 10.1021/acs.jmedchem.1c02002.
Zhiqi Feng  1 ,  Jiehao Xiang  1 ,  Hui Liu  1 ,  Jiaxin Li  1 ,  Xiangrui Xu  1 ,  Gang Sun  1 ,  Runan Zheng  1 ,  Shangran Zhang  1 ,  Junlong Liu  1 ,  Shanlin Yang  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. State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, China.
PMID: 35060744 DOI: 10.1021/acs.jmedchem.1c02002
Abstract

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. Other reported PPARα/δ dual agonists either exhibited limited potency or had unbalanced PPARα/δ agonistic activity. Herein, we report a series of novel triazolone derivatives as PPARα/δ dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC50 = 7.0 nM; PPARδ EC50 = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-agonist interaction. H11, which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or Other inflammatory and fibrotic diseases.

Products