Molecular-modeling based design, synthesis, and activity of substituted piperidines as γ-secretase inhibitors

A new series of γ-secretase inhibitors was designed using a ROCS search to identify likely scaffolds. Alzheimer’s disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Aβ) in the brain. Inhibition of γ-secretase, one of the enzymes responsible for Aβ production, may be a useful strategy for the treatment of AD. Described below is a series of γ-secretase inhibitors designed from a scaffold identified by a ROCS [ J. Comput. Chem. 1996, 17, 1653] search of the corporate database.