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

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.