Pharmacological Strategies for Inhibition of Thrombin Activity

Abstract

For decades, the options for therapeutic anticoagulation were limited to unfractionated heparin (UFH) and vitamin K antagonists (VKA), and their well-known limitations had to be accepted. With the introduction of the various LMWHs, the short-term anticoagulation could be much improved. The heparins delivered the proof of concept that FXa and thrombin represent suitable targets for therapeutic anticoagulation. Consequently, the search for new anticoagulants focus on inhibitors of thrombin or FXa. Apart from the VKA, the anticoagulants presently available or in an advanced stage of development can thus be divided in two classes: One are the glyco-anticoagulants with the natural sulfated glycosaminoglycans (GAGs) (UFH, LMWHs, and danaparoid) and the synthetic oligosaccharides (OS) (fondaparinux, idraparinux, and SR123781A). The other class are the xenobiotic anticoagulants, i.e. proteins and synthetic chemical entities. Die glyco-anticoagulants act partially (GAGs) or exclusively (oligosaccharides) by catalysing antithrombin, whereas the xenobiotic anticoagulants are direct inhibitors of either thrombin or FXa. At present, three direct thrombin inhibitors (DTI) (lepirudin, argatroban, and bivalirudin) are clinically used for limited indications, whereas there is still no direct FXa inhibitor available. The DTI ximelagatran represented the first oral anticoagulant since the introduction of VKA, but was withdrawn due to safety concerns. Among numerous drug candidates in the clinical development, two orally active anticoagulants dabigatran etexilate, a DTI, and rivaroxaban, the direct FXa inhibitor, are in the most advanced stage of development and may allow a paradigm change in anticoagulation in the foreseeable future. This review describes the pharmacological profile of all these anticoagulants.

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…Progress in thrombin inhibitor research and development was reviewed recently in this journal 46,47 and elsewhere. 22 In this review, the progress in fXa inhibitors over the years and an update on activity in the field since recent reviews 20,21 will be detailed.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18][19] In this article, a more comprehensive review of fXa inhibitors will be delineated, rather than an incremental update. [20][21][22] This review will first provide an overview on coagulation models and agents that affect coagulation. Then, it will focus on the medicinal chemistry of fXa inhibitors and how the inhibitors have evolved over the years.…”

Argatroban for Preventing Occlusion and Restenosis after Extracranial Artery Stenting

“…Argatroban can also inhibit soluble and postclotting thrombin which binds to fibrin or blood clot, and is better than heparin and other direct thrombin inhibitors [27]. Furthermore, other advantages include antiplatelet effect by reducing the thrombin-mediated activation of platelets [28], the protective effect of endothelial cells [29], and downregulation of various inflammatory and thrombotic cytokines [30]. …”

Dabigatran Etexilate: A Novel Oral Thrombin Inhibitor for Thromboembolic Disease

“…17, 18 Following oral administration, dabigatran etexilate is completely hydrolyzed to the active dabigatran, which binds reversibly to thrombin with high affinity and specificity. 7 Unlike the intravenous bivalent DTIs, lepirudin and bivalirudin, which require binding to both the active site as well as exosites on thrombin, univalent dabigatran binds to the active site. 18 By binding solely to the active site, dabigatran inactivates fibrin-bound and unbound thrombin, resulting in disruption of the coagulation cascade.…”

“…18 By binding solely to the active site, dabigatran inactivates fibrin-bound and unbound thrombin, resulting in disruption of the coagulation cascade. 7 Currently, no known antidote exists for toxicity resulting from dabigatran or its prodrug. In overdose or serious bleeding situations, dabigatran discontinuation is indicated followed immediately by supportive measures.…”