Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease.
10.1016/j.apsb.2025.02.030
- Author:
Zhipei SANG
1
;
Shuheng HUANG
2
;
Wanying TAN
3
;
Yujuan BAN
1
;
Keren WANG
4
;
Yufan FAN
5
;
Hongsong CHEN
6
;
Qiyao ZHANG
2
;
Chanchan LIANG
2
;
Jing MI
4
;
Yunqi GAO
6
;
Ya ZHANG
5
;
Wenmin LIU
4
;
Jianta WANG
1
;
Wu DONG
6
;
Zhenghuai TAN
7
;
Lei TANG
1
;
Haibin LUO
2
Author Information
1. 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.
2. Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
3. Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China.
4. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China.
5. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
6. College of Animal Science and Technology Inner Mongolia Minzu University, Tongliao, Inner Mongolia 028000, China.
7. Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China.
- Publication Type:Journal Article
- Keywords:
Alzheimer's disease;
Mechanism of action;
Pharmacodynamic studies;
Pharmacokinetic studies;
Selective BuChE inhibitor
- From:
Acta Pharmaceutica Sinica B
2025;15(4):2134-2155
- CountryChina
- Language:English
-
Abstract:
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 μmol/L, huBuChE IC50 = 0.066 μmol/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.
