Sang Zhipei, Huang Shuheng, Tan Wanying, Ban Yujuan, Wang Keren, Fan Yufan, Chen Hongsong, Zhang Qiyao, Liang Chanchan, Mi Jing, Gao Yunqi, Zhang Ya, Liu Wenmin, Wang Jianta, Dong Wu, Tan Zhenghuai, Tang Lei, Luo Haibin
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China.
Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
Acta Pharm Sin B. 2025 Apr;15(4):2134-2155. doi: 10.1016/j.apsb.2025.02.030. Epub 2025 Feb 28.
Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound , a selective reversible BuChE inhibitor (BuChE IC = 0.049 μmol/L, BuChE IC = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.
阿尔茨海默病（AD）是老年人中常见的神经退行性疾病，丁酰胆碱酯酶（BuChE）已成为一个潜在的治疗靶点。在本研究中，我们报告了化合物 的研发情况，该化合物是一种选择性可逆性BuChE抑制剂（BuChE IC = 0.049 μmol/L，BuChE IC = 0.066 μmol/L），通过广泛的虚拟筛选和先导化合物优化而确定。化合物 显示出良好的血脑屏障通透性、良好的类药性质和显著的神经保护功效。此外， 在斑马鱼AD模型和东莨菪碱诱导的小鼠认知障碍中表现出显著的治疗效果。进一步研究发现， 显著改善了APP/PS1转基因小鼠的认知功能。蛋白质组学分析表明， 显著提高了极低密度脂蛋白受体（VLDLR）的表达水平，为其对Reelin介导的信号通路的潜在调节作用提供了有价值的见解。因此，化合物 成为一种新型强效的用于治疗AD的BuChE抑制剂，对进一步探索其作用机制和治疗应用具有重要意义。
