Design, synthesis, and biological evaluation of piperazine derivatives as pan-PPARs agonists for the treatment of liver fibrosis

  • Eur J Med Chem. 2024 Mar 20:269:116344. doi: 10.1016/j.ejmech.2024.116344.
Gang Sun  1 ,  Zhiqi Feng  2 ,  Yufan Kuang  1 ,  Zhuoxin Fu  1 ,  Yanyan Wang  2 ,  Xing Zhao  1 ,  Fengqin Wang  2 ,  Hongbin Sun  2 ,  Haoliang Yuan  3 ,  Liang Dai  4
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing, 401135, China.
  • 3. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 4. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing, 401135, China. Electronic address: [email protected].
PMID: 38522113 DOI: 10.1016/j.ejmech.2024.116344
Abstract

Liver fibrosis is commonly occurred in chronic liver diseases, but there is no approved drug for clinical use. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) could not only regulate metabolic homeostasis but also possess anti-inflammatory and antifibrotic effects, and pan-PPARs agonist was considered as a potential anti-liver fibrosis agent. In this study, a series of novel piperazine pan-PPARs agonists were developed, and the preferred compound 12 displayed potent and well-balanced pan-PPARs agonistic activity. Moreover, compound 12 could dose-dependently stimulate the PPARs target genes expression and showed high selectivity over Other related nuclear receptors. Importantly, compound 12 exhibited excellent pharmacokinetic profiles and good anti-liver fibrosis effects in vivo. Collectively, compound 12 holds promise for developing an anti-liver fibrosis agent.

Keywords
Liver fibrosis; Nuclear receptor; PPARs; Piperazine.
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