Conformationally rigid N-acyl-5-alkyl-L-prolyl-pyrrolidines as prolyl oligopeptidase inhibitors

In the N-acyl-(L)-prolyl-pyrrolidine type of prolyl oligopeptidase inhibitors the L-prolyl group was replaced by different 5-alkyl-(L)-prolyl groups, resulting in a series of N-acyl-5-alkyl-(L)-prolyl-pyrrolidines. Since N-amides of 5-alkyl-(L)-prolines are conformationally more rigid than those of (L)-proline, the main objective was to make more rigid prolyl oligopeptidase inhibitors. In the series of compounds where the N-acyl group was a Boc group, the 5(R)-tert-butyl group increased the potency strongly. A similar effect was not observed for the 5(S)-tert-butyl group. In the series of compounds where the N-acyl group was a 4-phenylbutanoyl group, the 5(R)-tert-butyl, 5(R)-methyl and 5(S)-methyl groups did not have an effect on the potency [the 5(S)-tert-butyl group was not tested in this series]. As an additional effect, the 5-tert-butyl groups increased the log P of the compounds 1.5 log units, which might be beneficial when targeting the compounds to the brain. (C) 2003 Elsevier Ltd. All rights reserved.