Chen_2024_Eur.J.Med.Chem_272_116463

Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with beta-amyloid (Abeta) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE inhibitor S21-1011 (eqBChE IC(50) = 0.059 +/- 0.006 microM, hBChE IC(50) = 0.162 +/- 0.069 microM), which presented satisfactory druggability and therapeutic efficacy in AD models. In pharmacokinetics (PK) studies, S21-1011 showed excellent blood-brain barrier (BBB) permeability, metabolism stability and high oral-bioavailability. In pharmacodynamic (PD) studies, it protected neural cells from toxicity and inflammation stimulation in vitro. Besides, it also exerted anti-inflammatory effect and alleviated cognitive impairment in mice models induced by lipopolysaccharides (LPS) and Abeta. Generally, this compound has been confirmed to function as a neuroprotector and cognition improver in various AD pathology-like models. Therefore, S21-1011, a novel potent BChE inhibitor, could be considered as a potential anti-AD candidate worthy of more profound investigation.