4-Substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors

The protease γ-secretase plays a pivotal role in the synthesis of pathogenic amyloid-β in Alzheimer’s disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based γ-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Aβ(40) lowering in vivo (e.g., compound 32, MED 1 mg/kg p.o. in APP-YAC mice).

Graphical abstractStudies leading to the identification of the orally active γ-secretase inhibitor 32 are described. This compound demonstrated lowering of central Aβ(40) in a rodent model with a MED of 1 mg/kg.Figure optionsDownload full-size imageDownload as PowerPoint slide