Amine-containing donepezil analogues as potent acetylcholinesterase inhibitors with increased polarity

Functional dyspepsia (FD) is a gastrointestinal disorder characterized by postprandial fullness, upper abdominal bloating, and early satiation. Peripheral acetylcholinesterase (AChE) inhibitors such as acotiamide have shown efficacy in FD treatment, but their limited affinity towards the enzyme has hindered their effectiveness. Conversely, AChE inhibitors developed for Alzheimer's disease have high potency but exhibit strong central activity, making them unsuitable for FD treatment. In this study, we developed potent AChE inhibitors based on a donepezil and a phthalimide scaffold that contain additional amine groups. Our compounds demonstrate IC₅₀ values in the low to mid-nanomolar range. Computational modelling was employed to determine important molecular interactions with AChE. The compounds show low membrane permeability, which indicates a significantly reduced central activity. These findings suggest that the developed inhibitors could potentially serve as promising treatments for functional dyspepsia.