Amino Acids and Peptides. LIII. Synthesis and Biological Activities of Some Pseudo-Peptide Analogs of PKSI-527, a Plasma Kallikrein Selective Inhibitor : The Importance of the Peptide Backbone

Abstract

Pseudo-peptide analogs of trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanyl-4-aminophenyl acetic acid (PKSI-527, plasma kallikrein selective inhibitor), in which an amide bond (peptide bond) has been replaced by a CH₂-NH bond, i.e. trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanyl-Ψ(CH₂-NH)-4-aminophenyl acetic acid (I), trans-4-aminomethylcyclohexanecarbonyl-Ψ(CH₂-NH)-L-phenylalanyl-4-aminophenyl acetic acid (II) and trans-4-aminomethylcyclohexanecarbonyl-D-phenylalanyl-Ψ(CH₂-NH)-4-aminophenyl acetic acid (III) were synthesized. These pseudo-peptide analogs did not exhibit any detectable inhibitory activity against plasma kallikrein (PK), plasmin (PL), urokinase (UK), thrombine (TH) or trypsin (TRY). These results indicate that both carbonyl groups in the PKSI-527 are important for the manifestation of potent inhibitory activity against plasma kallikrein.