2,6-Disubstituted N-arylsulfonyl piperidines as γ-secretase inhibitors

A novel piperidine series of γ-secretase inhibitors, potentially useful for the treatment of Alzheimer’s disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC50’s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.

Graphical abstractA novel piperidine series of γ-secretase inhibitors, potentially useful for the treatment of Alzheimer’s disease, is disclosed.Figure optionsDownload full-size imageDownload as PowerPoint slide