Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease
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 <b>8e</b>, a selective reversible BuChE inhibitor (<i>eq</i>BuChE IC<sub>50</sub> = 0.049 μmol/L, <i>hu</i>BuChE IC<sub>50</sub> = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound <b>8e</b> demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, <b>8e</b> exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, <b>8e</b> significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that <b>8e</b> 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 <b>8e</b> 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.
Authors
- Jing Mi (ORCID: https://orcid.org/0000-0002-9918-6807)
- Shuheng Huang (ORCID: https://orcid.org/0000-0001-8552-7319)
- Zhipei Sang (ORCID: https://orcid.org/0000-0001-7254-5518)
- Yunqi Gao (ORCID: https://orcid.org/0009-0003-0599-8383)
- Yufan Fan (ORCID: https://orcid.org/0000-0003-3611-0191)
- Wu Dong
- Hai‐Bin Luo (ORCID: https://orcid.org/0000-0002-2163-0509)
- Wanying Tan
- Yujuan Ban
- Jianta Wang (ORCID: https://orcid.org/0000-0002-2007-0925)
- Ya Zhang (ORCID: https://orcid.org/0000-0001-9060-3777)
- Zhenghuai Tan (ORCID: https://orcid.org/0000-0002-7373-6356)
- Hongsong Chen (ORCID: https://orcid.org/0000-0002-2084-8653)
- Chaoyang Liang (ORCID: https://orcid.org/0000-0002-3296-2816)
- Keren Wang (ORCID: https://orcid.org/0000-0001-9892-2051)
- Qiyao Zhang (ORCID: https://orcid.org/0000-0002-3235-7093)
- Lei Tang (ORCID: https://orcid.org/0009-0003-8066-9811)
- Wenmin Liu
Institutions
- Inner Mongolia University for Nationalities (CN)
- Guiyang Medical University (CN)
- Hainan University (CN)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Nanyang Normal University (CN)
- Anyang Normal University (CN)
- Sichuan Academy of Traditional Chinese Medicine (CN)
Publication Details
- Journal
- Acta Pharmaceutica Sinica B
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1016/j.apsb.2025.02.030
- Citations
- 10
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 13.94