Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases β-cleavage of amyloid precursor protein and amyloid-β production in vivo

Generation and deposition of the amyloid β (Aβ) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and γ-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Aβ, is an...

Full description

Saved in:
Bibliographic Details
Published in:Journal of neurochemistry 2007-02, Vol.100 (3), p.802-809
Main Authors: Hussain, Ishrut, Hawkins, Julie, Harrison, David, Hille, Christopher, Wayne, Gareth, Cutler, Leanne, Buck, Tania, Walter, Daryl, Demont, Emmanuel, Howes, Colin, Naylor, Alan, Jeffrey, Philip, Gonzalez, Maria I, Dingwall, Colin, Michel, Anton, Redshaw, Sally, Davis, John B
Format: Article
Language:English
Subjects:
Administration, Oral
Adult and adolescent clinical studies
Alzheimer disease
Alzheimer Disease - drug therapy
Alzheimer Disease - metabolism
Alzheimer Disease - physiopathology
Alzheimer's disease
Amyloid beta-Peptides - biosynthesis
Amyloid beta-Protein Precursor - chemistry
Amyloid beta-Protein Precursor - metabolism
amyloid precursor protein
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - metabolism
Animals
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - metabolism
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Biological and medical sciences
Brain - drug effects
Brain - metabolism
Brain - physiopathology
Cell Line, Tumor
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Disease Models, Animal
Down-Regulation - drug effects
Down-Regulation - physiology
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Humans
Male
Medical sciences
Mice
Mice, Transgenic
Neurology
Organic mental disorders. Neuropsychology
p-glycoprotein
Peptides - metabolism
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
secretase
TASTPM
Thiazines - chemical synthesis
Thiazines - pharmacology
Thiazines - therapeutic use
Treatment Outcome
β-site amyloid precursor protein cleaving enzyme 1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Generation and deposition of the amyloid β (Aβ) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and γ-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Aβ, is an attractive therapeutic approach for the treatment of Alzheimer's disease. We have designed a selective non-peptidic BACE-1 inhibitor, GSK188909, that potently inhibits β-cleavage of APP and reduces levels of secreted and intracellular Aβ in SHSY5Y cells expressing APP. In addition, we demonstrate that this compound can effectively lower brain Aβin vivo. In APP transgenic mice, acute oral administration of GSK188909 in the presence of a p-glycoprotein inhibitor to markedly enhance the exposure of GSK188909 in the brain decreases β-cleavage of APP and results in a significant reduction in the level of Aβ40 and Aβ42 in the brain. Encouragingly, subchronic dosing of GSK188909 in the absence of a p-glycoprotein inhibitor also lowers brain Aβ. This pivotal first report of central Aβ lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease.
ISSN:0022-3042
1471-4159
DOI:10.1111/j.1471-4159.2006.04260.x