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Semin Thromb Hemost 1997; 23(6): 493-501
DOI: 10.1055/s-2007-996127
Copyright © 1997 by Thieme Medical Publishers, Inc.

Enzyme-Controlling Medicines: Introduction

Shosuke Okamoto* , Akiko Hijikata-Okunomiya† , Keiko Wanaka* , Yoshio Okada‡ , Utako Okamoto*
  • From the *Kobe Research Projects on Thrombosis and Haemostasis, Tarumi-ku,
  • †Faculty of Health Science, Kobe University School of Medicine, Suma-ku, and
  • ‡Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe, Japan.
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Publication History

Publication Date:
08 February 2008 (online)

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Abstract

A short history of the research work of S. Okamoto and co-workers, for the previous 50 years, is briefly described. In the 1950s, when the physiologic role of fibrinolysis had not been established, they began to seek for compounds that inhibit the action of plasmin. They examined approximately 200 lysine derivatives and discovered epsilon aminocaproic acid (EACA) and tranexamic acid (t-AMCHA).

In the 1970s, we selected thrombin as the target enzyme to be controlled; structure-activity relationship studies, taking arginine as the skeleton structure, led to the discovery of the selective thrombin inhibitor No. 205 (4-ethyl-l-[N2-(5-dimethylamino-1-naphthalenesulfonyl)-L-arginyl]-1-piperidine), and further attempts to minimize the toxicity finally led to No. 805 (argatroban, MD-805, (2R,4R)-4-methyll(N2-[(3-methyl-l,2,3,4-tetrahydro-8-quinolinyl)-sulfonyl]-L-arginyl)-2-piperidine carboxylic acid). Argatroban, without any cofactor, inhibits thrombin competitively. The high selectivity of the action of argatroban is promising for treating thrombosis in clinical practice. More recently, taking advantage of our knowledge obtained through previous studies, active center-directed plasmin inhibitors and a selective inhibitor of kallikrein have been found.

Keywords:

Thrombin inhibitors - plasmin inhibitors - argatroban - epsilon aminocaproic acid (EACA) - tranexamic acid (t-AMCHA)

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