Poststatin, a New Inhibitor of Prolyl Endopeptidase: VIII. Endopeptidase Inhibitory Activity of Non-peptidyl Poststatin Analogues

Non-peptidyl poststatin analogues, (S)-N-substituted-2-[2-1-acylpyrrolidinyl)]-2-oxoacetamides were synthesized and examined for their inhibitory activity against prolyl endopeptidase and cathepsin B in vitro. Many compounds showed stronger activity than natural poststatin, a pentapeptide. Among them, (S)-N-cyclohexyl-2-oxo-2-[2-(1-(3-phenoxybenzoyl)pyrrolidinyl)]acetamide (22) and (S)-N-cyclohexyl-2-[2-(1-(2-naphthoyl)pyrrolidinyl)]-2-oxoacetamide (19) indicated IC50 value of 5.8 and 8.2ng/ml for prolyl endopeptidase inhibition respectively. None of these compounds possess significant inhibitory activities against cathepsin B, a cysteine protease. These results indicate that these compounds are more selective inhibitors against prolyl endopeptidase than is natural poststatin.