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.