Organic & Biomolecular Chemistry 2005-07-07

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

Gilles Quéléver, Philippe Kachidian, Christophe Melon, Cédrik Garino, Younes Laras, Nicolas Pietrancosta, Mahmoud Sheha, Jean Louis Kraus

文献索引：Org. Biomol. Chem. 3(13) , 2450-7, (2005)

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摘要

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic Abeta peptides, is an attractive approach for the treatment of Alzheimer's disease. We designed a gamma-secretase inhibitor bearing an ascorbic acid moiety which allows a specific delivery of the drug to the brain. Through, on the one hand, Abeta peptide production measurements by specific in vitro assays (gamma-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 gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with a low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.