Diaminocyclopentane-derived -GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer's disease

We developed potent and selective aminocyclopentane-derived inhibitors of human O-N -acetyl-β- d -glucosaminidase (OGA) implicated in Alzheimer's disease. For example compound 13 was a nanomolar OGA inhibitor with 92 000-fold selectivity over human HexB. It was non-toxic and increased protein O -GlcNAcylation in the culture of murine neural cells, showing new alternatives in the treatment of tauopathies. We report the synthesis and testing of a novel type (new lead structure) of powerful and highly selective human O-N -acetyl-β- d -glucosaminidase (enzyme associated with Alzheimer's disease) inhibitors that are not based on transition state mimetics.