Okamoto's Strategy to Develop Argatroban: An Innovative Concept for the Future

ABSTRACT

Argatroban, the world's first direct thrombin inhibitor, developed by Shosuke Okamoto et al, is based on three development concepts: “exceeding global standards,” “avoiding current trends in research,” and “exploring drugs.” Okamoto sought compounds that strongly and selectively inhibited thrombin throughout his research on thrombin inhibitors. Compounds that selectively inhibit a specific enzyme can be used as a powerful tool to elucidate the physiological and pathological roles of that enzyme. As of January 2008, argatroban has been approved in 12 countries including Japan and used in several patients with chronic arterial thrombosis, acute cerebral thrombosis, and heparin-induced thrombocytopenia (HIT). Throughout his 60 years of research, Okamoto nurtured the belief of “science for the well-being of humankind,” leading him to research plasmin inhibitors and thrombin inhibitors. In the spirit of his research, we continue to make contributions for the betterment of humankind.

KEYWORDS

Thrombin inhibitor - plasmin inhibitor - heparin-induced thrombocytopenia - anticoagulants - argatroban

REFERENCES

• 1 Okamoto S. British Patent 770,693, 1957. U.S. Patent 2.939.817, 1960. 
• 2 Okamoto S. Plasmin and antiplasmin.  Keio J Med. 1959;  8 211-217
• 3 Okamoto S, Okamoto U. Amino-methyl-cyclohexane-carboxylic acid: AMCHA, a new potent inhibitor of the fibrinolysis.  Keio J Med. 1962;  11 105-115
• 4 Okamoto S, Sato S, Takada Y, Okamoto U. An active stereo-isomer (trans-form) of AMCHA and its antifibrinolytic (antiplasminic) action in vitro and in vivo.  Keio J Med. 1964;  13 177-185
• 5 Okamoto S, Hijikata A, Kikumoto R et al.. Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805. The importance of stereo-structure of its hydrophobic carboxamide portion.  Biochem Biophys Res Commun. 1981;  101 440-446
• 6 Okamoto S, Hijikata-Okunomiya A. Synthetic selective inhibitors of thrombin.  Methods Enzymol. 1993;  222 328-340
• 7 Okamoto S, Wanaka K, Hijikata-Okunomiya A. In vitro and in vivo properties of synthetic inhibitors of thrombin: recent advances. In: Cleason G, Scully M, Kakkar V, et al The Design of Synthetic Inhibitors of Thrombin. New York, NY; Plenum Press 1993
• 8 Tanabe T, Mishima Y, Furukawa K et al.. Clinical results MD-805, antithrombin agent, on chronic arterial occlusion. A multicenter cooperative study.  J Clin Ther Med. 1986;  2 1645-1655
• 9 Kobayashi S, Tazaki Y. Effect of the thrombin inhibitor argatroban in acute cerebral thrombosis.  Semin Thromb Hemost. 1997;  23 531-534
• 10 Lewis B E, Wallis D E, Berkowitz S D et al.. ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.  Circulation. 2001;  103 1838-1843
• 11 Akiyama H, Ikeda K, Kondo H, McGeer P L. Thrombin accumulation in brains of patients with Alzheimer's disease.  Neurosci Lett. 1992;  146 152-154
• 12 Morris R, Winyard P G, Blake D R, Morris C J. Thrombin in inflammation and healing: relevance to rheumatoid arthritis.  Ann Rheum Dis. 1994;  53 72-79