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Bioorg Med Chem. 2009 Feb 15;17(4):1600-13. doi: 10.1016/j.bmc.2008.12.067. Epub 2009 Jan 6.

Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase.

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  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.

Abstract

To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC(50)=0.567 microM; AChE: IC(50)=1.83 microM), and also showed excellent inhibitory effects on Abeta production of APP transfected HEK293 cells (IC(50)=98.7 nM) and mild protective effect against hydrogen peroxide (H(2)O(2))-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Abeta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.

PMID:
19162488
[PubMed - indexed for MEDLINE]
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