Serine proteases as targets for antithrombotic therapy

Pathological activation of the hemostatic system, resulting in thromboembolic complications, is a major cause of morbidity and mortality. Unfractionated heparins and low-molecular-weight heparins, both suitable only for parenteral administration, as well as vitamin K antagonists, represent the current cornerstone of antithrombotic therapy. Although orally active and very efficacious, the latter class of drugs has a narrow therapeutic window and requires frequent monitoring. Due to their apparent pivotal role in the coagulation cascade, the serine proteases factor Xa and thrombin have attracted the greatest attention in thrombosis research. The recently launched fondaparinux, an antithrombin-III-dependent pentasaccharide and highly selective factor Xa inhibitor, has demonstrated impressive clinical results and may play an important role in the future. On the other hand, the search for low-molecular-weight, orally active direct serine protease inhibitors has been the focus of intense research for more than a decade. However, only a very limited number of compounds are under late clinical development to date. The most advanced compound, the orally active, selective thrombin inhibitor ximelagatran, is in the preregistration phase for the treatment of deep vein thrombosis. Factor a and factor IXa have gained less attention as pharmacological targets, factor XIa and factor XIIa play only a minor role in thrombosis research.