Thiazolidine derivatives as potent inhibitors specific for prolyl endopeptidase.

A series of N-blocked L-proline-containing compounds and their derivatives were synthesized. Their inhibitory activities for prolyl endopeptidase from bovine brain were examined and compared with that of N-benzyloxycarbonyl-L-prolyl-L-prolinal, which is the most effective enzyme inhibitor hitherto reported. Introduction of a sulfur atom into pyrrolidine ring quite effectively increased the inhibitory activity: replacement of pyrrolidine with thiazolidine or thiazolidine aldehyde (thioprolinal) and conversion of L-proline to L-thioproline residue resulted in increase in the inhibitory activity. Thus, N-benzyloxycarbonyl-L-thioprolyl-thiazolidine (Z-Thiopro-thiazolidine) and Z-L-Thiopro-L-thioprolinal showed Ki values of 0.36 and 0.01 nM, respectively, for prolyl endopeptidase from bovine brain; both values were significantly lower than that of Z-Pro-prolinal (Ki, 3.7 nM).