Highly functionalized diaminocyclopentanes: A new route to potent and selective inhibitors of human O-GlcNAcase

[Display omitted] •Design and synthesis of new reversible diaminocyclopentanoid O-GlcNAcase inhibitors.•Systematic investigation of individual modifications influencing the inhibitory activity.•Activities and selectivities are explained based on molecular modeling.•Therapeutic benefits for treatment of tauopathies may be feasible. A new class of compounds inhibiting de-O-glycosylation of proteins has been identified. Highly substituted diaminocyclopentanes are impressively selective reversible non-transition state O-β-N-acetyl-d-glucosaminidase (O-GlcNAcase) inhibitors. The ease of preparative access and remarkable biological activities provide highly viable leads for the development of anti-tau-phosphorylation agents with a view to eventually ameliorating Alzheimer's disease.