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Generation and deposition of the amyloid [beta] (A[beta]) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and [gamma]-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of A[beta], 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 [beta]-cleavage of APP and reduces levels of secreted and intracellular A[beta] in SHSY5Y cells expressing APP. In addition, we demonstrate that this compound can effectively lower brain A[beta]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 [beta]-cleavage of APP and results in a significant reduction in the level of A[beta]40 and A[beta]42 in the brain. Encouragingly, subchronic dosing of GSK188909 in the absence of a p-glycoprotein inhibitor also lowers brain A[beta]. This pivotal first report of central A[beta] lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease.

(C) 2007 International Society for Neurochemistry