The preparation and in vitro prolyl endopeptidase (PEP) inhibitory activity of a series of alpha-keto heterocyclic compounds is described. The design is based on the introduction of alpha-keto heterocycles at the C-terminal end of substrate-like peptides. Many of the compounds including those substituted with thiazole, benzothiazole, benzoxazole, imidazole, and pyridine groups exhibit IC50 potencies of PEP inhibition at nanomolar levels. Structure-activity studies of the C-terminal heterocyclic groups indicate the importance of an sp2 nitrogen atom at a beta-position from the adjoining ketone carbonyl group. This heterocyclic nitrogen atom would provide a critical hydrogen-bond interaction with the histidine residue of the catalytic triad in PEP. Our inhibitors would extend the generality of the alpha-keto heterocycle design to another serine protease.

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