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.

Glycogroup Institute of Chemistry and Technology of Biobased Systems Graz University of Technology Stremayrgasse 9 A 8010 Graz Austria

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 14220 Prague 4 Czech Republic

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