Enzyme-controlling medicines: Introduction
Enzyme-controlling medicines: Introduction
复制标题
DOI：
10.1055/s-2007-996127
复制
发表时间：
1997-01-01
影响因子：
5.7
通讯作者：
Okamoto, U
中科院分区：
文献类型：
--
作者：
Okamoto, S;Hijikata-Okunomiya, A;Okamoto, U
简要回顾了S、冈本及其同事近50年来的研究工作。20世纪50年代，当纤溶的生理作用尚未确定时，他们开始寻找抑制纤溶酶作用的化合物，他们检查了大约200个赖氨酸衍生物，发现了β-氨基己酸(EACA)和氨甲环酸(t-AMCHA)，在70年代，我们选择凝血酶作为控制的靶酶；以精氨酸为骨架结构的构效关系研究，导致了选择性凝血酶抑制剂No.205(4-ethyl-1-[N-2-(5-dimethylamino-1-naphthalenesulfonyl)-L-arginyl]-1-piperidine)，的发现，并进一步试图将毒性降至最低，最终得到了No.805(Argtreban，MD-805，(2R，4R)-4-methyl-1-(N-2-[(3-methyl-1，2，3，4-tetrahydro-8-quinolinyl)-sulfonyl]-L-arginyl)-2-piperidine羧酸)。阿加曲班在没有任何辅因子的情况下，竞争性抑制凝血酶。阿加曲班具有较高的选择性，有望在临床上用于治疗血栓形成。最近，利用我们通过先前研究获得的知识，活性中心定向的纤溶酶抑制物和激肽释放酶的选择性抑制物被发现。
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-1-[N-2-(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-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 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.