[摘要]:Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular pro-teinaceous plaques comprised primarily of beta-amyloid. gamma-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of beta-amyloid peptides; one of which, A beta 42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine gamma-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral A beta 42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of gamma-secretase inhibitors capable of lowering cerebral A beta 42 production in mice. (C) 2012 Elsevier Ltd. All rights reserved.