JNJ-40418677 is an inhibitor of gamma-secretase. JNJ-40418677 selectively reduced amyloid β 42 secretion in human neuroblastoma cells and rat primary neurones, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non-transgenic mice with JNJ-40418677 resulted in an excellent brain penetration of the compound and a dose- and time-dependent decrease of brain amyloid β 42 levels. Chronic treatment of Tg2576 mice (a mouse model of Alzheimer's disease) with JNJ-40418677 reduced brain amyloid β levels, the area occupied by plaques and plaque number in a dose-dependent manner compared with transgenic vehicle-treated mice.