Stone S R, Tapparelli C
Department of Haematology, University of Cambridge, UK.
J Enzyme Inhib. 1995;9(1):3-15. doi: 10.3109/14756369509040677.
For use as an antithrombotic agent, a thrombin inhibitor must be potent and specific, i.e., it should not significantly inhibit the proteases of the anticoagulation (activated protein C) and fibrinolytic systems (plasminogen activator and plasmin). Previous evaluation of potency and specificity has been based on inhibition constants (Ki values). However, consideration of the kinetic parameters for natural plasma serine protease inhibitors indicates that a low Ki value with thrombin is not sufficient; the inhibited complex must also form rapidly. Moreover, potent inhibition of activated protein C and plasmin could be tolerated providing the inhibited complex only forms slowly. An ideal profile of kinetic parameters with thrombin, activated protein C and plasmin is formulated and discussed in relation to various classes of thrombin inhibitors. Examination of kinetic data for thrombin inhibitors currently in clinical trials (hirudin and hirulog) indicates that they possess this ideal profile of kinetic parameters.
作为抗血栓形成剂使用时，凝血酶抑制剂必须强效且具有特异性，即它不应显著抑制抗凝系统（活化蛋白C）和纤溶系统（纤溶酶原激活剂和纤溶酶）的蛋白酶。以往对效力和特异性的评估基于抑制常数（Ki值）。然而，对天然血浆丝氨酸蛋白酶抑制剂动力学参数的考量表明，仅凝血酶的低Ki值是不够的；被抑制的复合物还必须快速形成。此外，只要被抑制的复合物形成缓慢，对活化蛋白C和纤溶酶的强效抑制是可以接受的。本文针对各类凝血酶抑制剂，制定并讨论了凝血酶、活化蛋白C和纤溶酶理想的动力学参数概况。对目前正在进行临床试验的凝血酶抑制剂（水蛭素和水蛭肽）的动力学数据检查表明，它们具有这种理想的动力学参数概况。
