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

作者：Zhiqi Feng, Jiehao Xiang, Hui Liu, Jiaxin Li, Xiangrui Xu, Gang Sun, Runan Zheng, Shangran Zhang, Junlong Liu, Shanlin Yang, Qing‐Long Xu, Xiaoan Wen, Haoliang Yuan, Hongbin Sun, Liang Dai · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.1c02002 · 被引用次数：30 · 研究领域：Peroxisome Proliferator-Activated Receptors、Liver Disease Diagnosis and Treatment、Hepatitis C virus research

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 EC 50 = 7.0 nM; PPARδ EC 50 = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC 50 = 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.