A drug library of 17200 compounds was screened to select small molecules that inhibit the secretion of amyloid β peptide (Aβ), the major component of Alzheimer disease senile plaques, from a human neuronal cell line. Twenty-nine hits were validated that decreased Aβ secretion by >40% at 10 μM, for a 0.17% hit rate. A lead hit was selected for further study based on its activity and low cytotoxicity, and it was found to inhibit Aβ secretion through activation of the α-secretase pathway. Twenty-four commercially available and 53 synthesized analogues were analyzed for activity. Selected analogues were evaluated for biological stability by incubation with hepatoma cells and for transcellular permeability using Caco-2 cell monolayers. The analogue with the best permeability was evaluated in 2-month old amyloid precursor protein transgenic mice and found to acutely reduce cerebral Aβ levels by 40% after a single iv administration. © 2010 American Chemical Society.