Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors.

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Hu Y, Zhang J, Chandrashankra O, Ip FC, Ip NY

Design, synthesis and evaluation of novel heterodimers of donepezil and huperzine fragments as acetylcholinesterase inhibitors.

Bioorg Med Chem. 2013 Feb 1;21(3):676-83. doi: 10.1016/j.bmc.2012.11.044. Epub 2012 Dec 6.

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23273608 [ View in PubMed

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Abstract

Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer's disease. Heterodimers comprised of dimethoxyindanone (from donepezil), hupyridone (from HupA), and connected with a multimethylene linker, were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers (RS,S)-17b (with a tetramethylene linker) exhibited the highest potency of inhibition towards AChE with an IC(50) value of 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Donepezil	Acetylcholinesterase	IC 50 (nM)	5.7	N/A	N/A	Details