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Potent β-Amyloid Modulators

Potent β-Amyloid Modulators Currently, the potential to interfere with the pathology of β-amyloid targeting a well-known drugable enzyme, the acetylcholinesterase (AChE), is opened. Peripheral or dual binding site inhibitors of AChE may simultaneously alleviate the cognitive and behavioral deficits in Alzheimer’s disease (AD) patients and, more importantly, act as disease-modifying agents delaying amyloid plaque formation. As part of a rational drug design program directed to find dual binding site AChE inhibitors, several families of compounds have been synthesized as potent AChE inhibitors. From these series, several drug candidates were selected based on their potent and selective inhibition of AChE (subnanomolar activity) and their interference with the β-amyloid aggregation in vitro (IC<sub>50</sub> in the low micromolar range). First in vivo data confirm our initial hypothesis. Oral treatment with NP-61 for 3 months is able to reverse the cognitive impairment (Morris water maze test) and to reduce plaque load in the brains of human amyloid precursor protein transgenic mice (Swedish mutation). These results suggest that NP-61, a potent β-amyloid modulator, is able to reverse the AD-like neurodegenerative phenotype in transgenic mice, indicating a promising disease-modifying agent for clinical application. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurodegenerative Diseases Karger

Potent β-Amyloid Modulators

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References (9)

Publisher
Karger
Copyright
© 2008 S. Karger AG, Basel
ISSN
1660-2854
eISSN
1660-2862
DOI
10.1159/000113688
Publisher site
See Article on Publisher Site

Abstract

Currently, the potential to interfere with the pathology of β-amyloid targeting a well-known drugable enzyme, the acetylcholinesterase (AChE), is opened. Peripheral or dual binding site inhibitors of AChE may simultaneously alleviate the cognitive and behavioral deficits in Alzheimer’s disease (AD) patients and, more importantly, act as disease-modifying agents delaying amyloid plaque formation. As part of a rational drug design program directed to find dual binding site AChE inhibitors, several families of compounds have been synthesized as potent AChE inhibitors. From these series, several drug candidates were selected based on their potent and selective inhibition of AChE (subnanomolar activity) and their interference with the β-amyloid aggregation in vitro (IC<sub>50</sub> in the low micromolar range). First in vivo data confirm our initial hypothesis. Oral treatment with NP-61 for 3 months is able to reverse the cognitive impairment (Morris water maze test) and to reduce plaque load in the brains of human amyloid precursor protein transgenic mice (Swedish mutation). These results suggest that NP-61, a potent β-amyloid modulator, is able to reverse the AD-like neurodegenerative phenotype in transgenic mice, indicating a promising disease-modifying agent for clinical application.

Journal

Neurodegenerative Diseases – Karger

Published: Jan 1, 2008

Keywords: β-Amyloid; Dual binding site acetylcholinesterase inhibitors; Alzheimer’s disease; Disease-modifying drug

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