2. Academic Validation
  3. Design, synthesis, and biological evaluation of piperazine derivatives as pan-PPARs agonists for the treatment of liver fibrosis

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

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: yhl@cpu.edu.cn.
  • 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: dailiang@cpu.edu.cn.
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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