Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 3, Pages 676-683Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.11.044
Keywords
Alzheimer's disease; Acetylcholinesterase; Heterodimer; Huperzine A
Funding
- Area of Excellence Scheme of the University Grants Committee of HKSAR [AoE/B-15/01]
- Hong Kong Jockey Club Charities Trust
- Innovation and Technology Fund of Hong Kong [ITS/246/09FP]
- Axis Biotech Pty Limited
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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 IC50 value of 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1 mM. (C) 2012 Elsevier Ltd. All rights reserved.
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