Development of Active Center-Directed Inhibitors against Plasmin

• Published in: Chemical & pharmaceutical bulletin Vol. 39; no. 9; pp. 2340 - 2346
• Main Authors: TENO, Naoki, WANAKA, Keiko, OKADA, Yoshio, TSUDA, Yuko, OKAMOTO, Utako, HIJIKATA-OKUNOMIYA, Akiko, NAITO, Taketoshi, OKAMOTO, Shosuke
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1991; Maruzen; Japan Science and Technology Agency
• Subjects: 4-aminomethylcyclohexanecarbonyllysine 4-benzoylanilide; 4-aminomethylcyclohexanecarbonyllysine 4-benzylpiperdine amide; Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; competitive inhibitor; design; Enzymes and enzyme inhibitors; Fibrinolysin - antagonists & inhibitors; Fundamental and applied biological sciences. Psychology; Hydrolases; Lys derivative; plasmin; structure-activity relationship; synthesis; Tra-Lys-4-methoxycarbonylanilide; Site specificity; Enzyme inhibitor; Structure activity relation; Enzyme; Active site; Plasmin
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.39.2340

Active center-directed inhibitors of plasmin were designed based on the structure of specific substrates of plasmin and then synthesized. Their effects on plasmin were examined and the structure-inhibitory activity relationship was studied. Nα-trans-4-Aminomethylcyclohexanecarbonyllysine 4-benzoylanilide (Tra-Lys-BZA) inhibited plasmin activities toward S-2251 and fibrin with IC50 values of 15 and 6.1 μM, respectively and Nα-trans-4-aminomethylcyclohexanecarbonyllysine 4-benzylpiperidine amide (Tra-Lys-BPP) did not show any detectable inhibitory activity. Moreover, it was revealed that Tra-Lys-4-methoxycarbonylanilide inhibited plasma kallikrein more potently than plasmin.