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)
