CONFORMATIONAL-ANALYSIS OF 2 INHIBITORS OF PROLYL-ENDOPEPTIDASE - COMPARISON OF 4-PHENYL-BUTYRYL-PYRROLIDINE AND OCTANOYL-PROLYL-PYRROLIDINE

The conformational analysis of two prolyl-endopeptidase (PEP) inhibito rs was performed. A molecular mechanics based random conformational se arch showed that 4-phenyl-butyryl-prolyl-pyrrolidine (1) is U-shaped i n most low-energy conformations. The results were compared with semiem pirical AM1 calculations. In contrast, the molecule octanoyl-prolyl-py rrolidine (2) has a linear alkyl-chain, although the U-shaped conforma tions, required for the same mechanism of action, can be easily attain ed. The results of conformational analyses were compared with those of NMR measurements. The common pharmacophore for these and several othe r PEP inhibitors was derived.