A new class of compounds, namely highly substituted diaminocyclopentane-l-lysine adducts, have been discovered as potent inhibitors of O-GlcNAcase, an enzyme crucial for protein de-O-glycosylation. These inhibitors exhibit exceptional selectivity and reversibility and are the first example of human O-GlcNAcase inhibitors that are structurally related to the transition state of the rate-limiting step with the "aglycon" still in bond-length proximity. The ease of their preparation, remarkable biological activities, stability, and non-toxicity make them promising candidates for the development of anti-tau-phosphorylation agents holding significant potential for the treatment of Alzheimer's disease.