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Issue 13, 2005
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Enhanced delivery of γ-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy

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Abstract

Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic Aβ peptides, is an attractive approach for the treatment of Alzheimer's disease. We designed a γ-secretase inhibitor bearing an ascorbic acid moiety which allows a specific delivery of the drug to the brain. Through, on the one hand, Aβ peptide production measurements by specific in vitro assays (γ-secretase cell free assay and cell based assay on HEK 293 APP transfected cells) and on the other hand through pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent γ-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug 2 will be mainly delivered to the CNS with a low diffusion in the peripheral tissues. Consequently the side effects of this γ-secretase inhibitor on the immune cells could be reduced.

Graphical abstract: Enhanced delivery of γ-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy

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Article information


Submitted
12 Apr 2005
Accepted
11 May 2005
First published
31 May 2005

Org. Biomol. Chem., 2005,3, 2450-2457
Article type
Paper

Enhanced delivery of γ-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy

G. Quéléver, P. Kachidian, C. Melon, C. Garino, Y. Laras, N. Pietrancosta, M. Sheha and J. Louis Kraus, Org. Biomol. Chem., 2005, 3, 2450
DOI: 10.1039/B504988A

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