Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease

被引:0
作者
Sang, Zhipei [1 ,2 ,3 ]
Huang, Shuheng [2 ,3 ]
Tan, Wanying [4 ]
Ban, Yujuan [1 ]
Wang, Keren [5 ]
Fan, Yufan [6 ]
Chen, Hongsong [7 ]
Zhang, Qiyao [2 ,3 ]
Liang, Chanchan [2 ,3 ]
Mi, Jing [5 ]
Gao, Yunqi [7 ]
Zhang, Ya [6 ]
Liu, Wenmin [5 ]
Wang, Jianta [1 ]
Dong, Wu [7 ]
Tan, Zhenghuai [8 ]
Tang, Lei [1 ]
Luo, Haibin [2 ,3 ]
机构
[1] Guizhou Med Univ, Guizhou Prov Engn Technol Res Ctr Chem Drug R&D, State Key Lab Discovery & Utilizat Funct Component, Guiyang 550004, Peoples R China
[2] Hainan Univ, Minist Educ, Key Lab Trop Biol Resources, Haikou 570228, Peoples R China
[3] Hainan Univ, One Hlth Inst, Sch Pharmaceut Sci, Haikou 570228, Peoples R China
[4] Sichuan Univ, Ctr Infect Dis, West China Hosp, Chengdu 610041, Peoples R China
[5] Nanyang Normal Univ, Coll Chem & Pharmaceut Engn, Nanyang 473061, Peoples R China
[6] Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China
[7] Inner Mongolia MINZU Univ, Coll Anim Sci & Technol, Tongliao 028000, Inner Mongolia, Peoples R China
[8] Sichuan Acad Chinese Med Sci, Inst Tradit Chinese Med Pharmacol & Toxicol, Chengdu 610041, Peoples R China
基金
中国国家自然科学基金; 海南省自然科学基金; 中国博士后科学基金;
关键词
Alzheimer's disease; Selective BuChE inhibitor; Pharmacokinetic studies; DERIVATIVES; DESIGN; MOUSE; POTENT;
D O I
10.1016/j.apsb.2025.02.030
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 8e, a selective reversible BuChE inhibitor (eqBuChE IC50 = 0.049 mmol/L, huBuChE IC50 = 0.066 mmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e 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 8e 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. <feminine ordinal indicator> 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
引用
收藏
页码:2134 / 2155
页数:22
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