Structure guided P1′ modifications of HEA derived β-secretase inhibitors for the treatment of Alzheimer’s disease

The synthesis and SAR of a series of BACE-1 hydroxyethyl amine inhibitors containing substitutions on a spirocyclobutyl moiety is described. Selectivity against cathepsin D, a related aspartyl protease with potential off target toxicity, and improved microsomal stability is exemplified.

The structure–activity relationship of the P1′ region of hydroxyethylamine inhibitors of β-secretase (BACE-1) is described.Figure optionsDownload as PowerPoint slide