Elsevier

Thrombosis Research

Volume 93, Issue 5, 1 March 1999, Pages 203-241
Thrombosis Research

State of the art article
Synthetic Inhibitors of Thrombin and Factor Xa: From Bench to Bedside

https://doi.org/10.1016/S0049-3848(98)00192-3Get rights and content

Section snippets

Structures of Inhibitors and Binding to the Target Enzymes

Synthetic thrombin inhibitors can be classified according to their chemical structures or the mechanism/kinetics of binding to the enzyme. The chemistry of synthetic thrombin inhibitors has been dealt with comprehensively in 1995 [5]; and a review referring also to the voluminous patent literature appeared in 1997 [9]. We will not attempt to cover completely the chemistry of all the structures reported since the list of compounds is extensive; structural data are available for many of them, and

Kinetics of Inhibition and Selectivity

In terms of enzyme kinetics, the problem as to the kind of inhibitor best suited for therapeutic purposes seems to be solved. Currently, development is centered on obtaining active site-directed competitive inhibitors with nanomolar Ki values. Irreversible binding, mediated by reactive groups, may bring about limitations with respect to selectivity and in vivo applicability. The importance of rapid binding for the anticoagulant activity of an inhibitor of thrombin was demonstrated in vitro and

Thrombin Inhibitors

From the pharmacological point of view, thrombin inhibitors, unlike other proteinase inhibitors, do not find a preformed, permanent systemic target in the organism. Instead, their specific binding site is present only when the target enzyme is generated from its zymogen in a temporally and locally limited process. The specific pharmacodynamic effect of a thrombin inhibitor is inhibition of the thrombin-catalyzed reactions and anticoagulation is considered the main resulting effect. Direct

Clinical Application of Synthetic Thrombin Inhibitors

The rationale of therapeutic use of thrombin inhibitors in cardiovascular patients is “antithrombotic effect by anticoagulation”, a concept based on several decades of experience with heparin and the vitamin K antagonists. Since thrombin is contributing to a variety of pathogenic mechanisms it is hoped that early intervention by direct thrombin inhibition may provide therapeutic advantages. The “first generation” thrombin inhibitors that have reached the stage of early or more advanced clinical

Perspectives

Design strategies for active site-directed inhibitors of thrombin and factor Xa have to focus not only on optimal binding to the target enzyme but also on finding positions in the inhibitor molecules tolerating a variety of groups suited for modifications that could modulate the physico-chemical properties and their fate in the body. Poor mucous membrane permeation and/or extensive hepatic first-pass effect have been elucidated as major obstacles for sufficient oral bioavailability of quite a

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