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. 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.