title: Substituted thiazolamide coupled to a redox delivery system: a new gamma-secretase inhibitor with enhanced pharmacokinetic profile.
abstract: Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic A beta peptides, is an attractive approach for the treatment of Alzheimer's disease. We have designed a new gamma-secretase thiazolamide inhibitor bearing a dihydronicotinoyl moiety as Redox Delivery System which allows specific delivery of the drug to the brain. Through, on the one hand, A beta 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, 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 low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.
authors.affiliation: INSERM U-623, Institut de Biologie du Developpement de Marseille, CNRS-INSERM-Universite de la Mediterranee, Laboratoire de Chimie Biomoleculaire, 13288 Marseille Cedex 09, France.
authors.forename: Younes
authors.initials: Y
authors.lastname: Laras
authors.forename: Gilles
authors.initials: G
authors.lastname: Quéléver
authors.forename: Cédrik
authors.initials: C
authors.lastname: Garino
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pietrancosta
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Sheha
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bihel
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kraus
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry; D016503:Drug Delivery Systems; D010450:Endopeptidases / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000737:chemistry; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000577:Amides; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D009539:Nicotinic Acids; D013844:Thiazoles; C038806:1,4-dihydropyridine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human