A fragment-based docking procedure followed by substructure search were used to identify active-site β-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC50 values less than 10 μM were measured in at least one of two different mammalian cell-based assays for 12 of the 72 purchased compounds. In particular, the phenylureathiadiazole 2 and the diphenylurea derivative 3 are promising lead compounds for β-secretase inhibition.