ABSTRACT
Introduction Improved understanding of the molecular mechanisms of blood coagulation has led to the development of new anticoagulants for the prevention and treatment of thromboembolic disorders in order to overcome the limitations of existing anticoagulants. These limitations include the need for coagulation monitoring and subsequent dose adjustment for vitamin K antagonists (Table 1), the difficulty of continuing prophylaxis out of hospital due to require parenteral administration for heparins, and the risk of heparin-induced thrombocytopenia (1). Various new anticoagulants target specific coagulation enzymes or different steps in the coagulation cascade, that is, the initiation of coagulation by factor VIIa/tissue factor (FVIIa/TF), its propagation by factors IXa, Xa and their cofactors, and the thrombin-mediated fibrin formation (2). The serine proteinase thrombin is the central enzyme in the coagulation pathway. It catalyzes the conversion of fibrinogen to fibrin by cleaving the peptide bond between arginine and glycine in the fibrinogen sequence GlyVal-Arg-Gly-Pro-Arg, activates the factors V, VIII, and XIII, and strongly stimulates platelet aggregation. Besides its procoagulant activities, thrombin also exhibits anticoagulant properties via the activation of the protein C pathway. Because of its pivotal role in the coagulation process, thrombin has been a target for the development of specific and selective inhibitors for many years (3). Intensive structure-based design over the last 20 years resulted in the development of numerous direct thrombin inhibitors (TIs), most of which have been peptidomimetic compounds that mimic the fibrinogen sequence interacting with the active site of thrombin (4). The new TIs bind directly to thrombin and block its interaction with different thrombin substrates. At present, the most important TIs that have been extensively evaluated for clinical use are the bivalent inhibitors, hirudin and bivalirudin, which interact with both the active site and the exosite-1 of thrombin in an irreversible and reversible manner,
respectively, as well as argatroban, which reversibly binds to the active site. Unfortunately because of their chemical structures, these new agents are not sufficiently absorbed after oral administration and have to be administered parenterally. Thus, they are less suitable for long-term anticoagulation. The development of orally effective, direct TIs seems to be a promising alternative to the existing direct or indirect anticoagulants for long-term use in patients with thromboembolic disorders. However, the design of those new drugs is difficult because different physicochemical properties are required for either the binding of a compound to the active site of thrombin or its absorption from the gastrointestinal tract (5). At present, various oral direct TIs are reported to be under development, of which ximelagatran and dabigatran etexilate are in a more advanced stage of clinical development (6,7).
