Synthesis of Active Center-Directed Peptide Inhibitors of Plasmin1)

Abstract

Active center-directed peptide inhibitors of plasmin were designed based on the structure of specific substrates of plasmin and synthesized by a conventional solution method. Their effects on plasmin were examined and the structure-activity relationship was studied. D-Ile-Phe-Lys-BZA (4-benzoylanilide) inhibited plasmin activities toward S-2251 and fibrin (IC50 0.069 mM and 0.18 mM respectively) but D-Ile–Phe–Lys–BPP (4-benzylpiperidine amide) was not inhibitory. However D-Ile–Phe–Lys–BZA was cleaved by plasmin to release benzoylaniline indicating that this type of peptide inhibitor is not stable to plasmin. It was found that Tos–Lys–pNA was not cleaved by palsmin and inhibited plasmin activity toward not only fibrin but also small peptide substrates and fibrinogen by blocking the active center of plasmin with some selectivity. In order to obtain potent and stable inhibitors of plasmin it is recommended to design them with reference to the structures of Tos–Lys–pNA and the specific substrate D-Ile–Phe–Lys–pNA. © 1988, The Pharmaceutical Society of Japan. All rights reserved.