Enzyme-controlling medicines: Introduction

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 comp ounds that inhibit the action of plasmin, They examined approximately 200 l ysine derivatives and discovered epsilon aminocaproic acid (EACA) and trane xamic acid (t-AMCHA), In the 1970s, we selected thrombin as the target enzyme to be controlled; s tructure-activity relationship studies, taking arginine as the skeleton str ucture, led to the discovery of the selective thrombin inhibitor No. 205 (4 -ethyl-1-[N-2-(5-dimethylamino-1-naphthalenesulfonyl)-L-arginyl]-1-piperidi ne), and further attempts to minimize the toxicity finally led to No. 805 ( argatroban, MD-805, (2R,4R)-4-methyl-1-(N-2-[(3-methyl-1,2,3,4-tetrahydro-8 -quinolinyl)-sulfonyl]-L-arginyl)-2-piperidine carboxylic acid). Argatroban , without any cofactor, inhibits thrombin competitively. The high selectivi ty of the action of argatroban is promising for treating thrombosis in clin ical practice. More recently, taking advantage of our knowledge obtained th rough previous studies, active center-directed plasmin inhibitors and a sel ective inhibitor of kallikrein have been found.