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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
Author(s) -
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.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04260.x
Subject(s) - amyloid precursor protein , amyloid precursor protein secretase , in vivo , p3 peptide , chemistry , pharmacology , genetically modified mouse , amyloid beta , alzheimer's disease , amyloid (mycology) , peptide , biochemistry , intracellular , transgene , medicine , biology , disease , gene , inorganic chemistry , microbiology and biotechnology
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 Aβ in 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.