Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer's disease
Zhipei Sang, Shuheng Huang, Wanying Tan, Yujuan Ban, Keren Wang, Yufan Fan, Hongsong Chen, Qiyao Zhang, Chanchan Liang, Jing Mi, Yunqi Gao, Ya Zhang, Wenmin Liu, Jianta Wang, Wu Dong, Zhenghuai Tan, Lei Tang, Haibin Luo
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 ( eq BuChE IC 50 = 0.049 μmol/L, hu BuChE IC 50 = 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.