Enhanced delivery of gamma-secretase inhibitor DAPT into the brain via an ascorbic acid mediated strategy.
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.
Quéléver
Gilles
G
INSERM U-623, Institut de Biologie du Développement de Marseille (CNRS-INSERM-Université de la Méditerranée), Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, case 907, 13288 Marseille Cedex 09, France.
Kachidian
Philippe
P
Melon
Christophe
C
Garino
Cédrik
C
Laras
Younes
Y
Pietrancosta
Nicolas
N
Sheha
Mahmoud
M
Louis Kraus
Jean
J
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D001205:Ascorbic Acid / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage* / Q000138:chemical synthesis; D016503:Drug Delivery Systems; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis; D006801:Humans; D010599:Pharmacokinetics
D016564:Amyloid beta-Protein Precursor; D004151:Dipeptides; D004791:Enzyme Inhibitors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D001205:Ascorbic Acid