Design, synthesis, and Biological evaluation of novel macrocyclic derivatives as potent ATP-citrate lyase inhibitors

  • Eur J Med Chem. 2025 Aug 5:292:117684. doi: 10.1016/j.ejmech.2025.117684.
Yongjun Zang  1 ,  Maoying Shi  1 ,  Luyang Tai  1 ,  Yuanyang Hu  1 ,  Yu Wang  1 ,  Runan Zheng  2 ,  Zhiqi Feng  3 ,  Haoliang Yuan  3 ,  Xiaoan Wen  4 ,  Liang Dai  5
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; Animal Experiment Center of China Pharmaceutical University, China Pharmaceutical University, Nanjing, 211198, China.
  • 3. 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.
  • 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].
  • 5. 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: 40315729 DOI: 10.1016/j.ejmech.2025.117684
Abstract

ATP-citrate lyase (ACLY) is a key lipogenic enzyme involved in the synthesis of fatty acid and Cholesterol, which converts cytosolic citrate to acetyl-CoA, a starting material for de novo lipogenesis. ACLY inhibitor is considered as potential therapeutic strategy for dyslipidemia and related diseases. In this study, we reported a series of novel macrocyclic derivatives as ACLY inhibitors, among them, compound 55 exhibited potent ACLY inhibitory activity (IC50 = 8.3 nM) and high binding affinity to ACLY. Notably, compound 55 demonstrated good pharmacokinetic profiles and potent in vivo hypolipidemic effect. Collectively, compound 55 deserved further development to provide potential candidate for treatment of hyperlipidemia and related diseases.

Keywords
ACLY; Enzyme; Hyperlipidemia; Macrocyclic derivatives.
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