Design, synthesis, and biological evaluation of imidazolidinone derivatives as potent PPARα/δ agonists for the treatment of cholestatic liver diseases

  • Eur J Med Chem. 2025 Mar 15:286:117284. doi: 10.1016/j.ejmech.2025.117284.
Zhuoxin Fu  1 ,  Xin Liu  1 ,  Wenhui Yu  1 ,  Yufan Kuang  1 ,  Fengqin Wang  1 ,  Zhiqiang Qian  1 ,  Qinglong Xu  2 ,  Liang Dai  3 ,  Zhiqi Feng  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. Electronic address: [email protected].
  • 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. Electronic address: [email protected].
PMID: 39827490 DOI: 10.1016/j.ejmech.2025.117284
Abstract

Cholestatic liver disease (CLD) represents a significant and growing public health concern, and there is a lack of effective therapeutic drug in clinical practice. Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for CLD. In this study, a series of novel imidazolidinone PPARα/δ agonists were developed, and the preferred compound 8 displayed potent and well-balanced agonistic activity. Compound 8 showed high selectivity over Other related nuclear receptors and effectively regulated the PPARα/δ target genes expression in mice. Notably, compound 8 demonstrated good pharmacokinetic profiles and potent in vivo anti-CLD effects. Collectively, compound 8 holds promise for developing an anti-CLD agent.

Keywords
Cholestatic liver disease; Imidazolidinone; Nuclear receptor; PPARs.
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