Oral, Direct Thrombin and Factor Xa Inhibitors: The Replacement for Warfarin, Leeches, and Pig Intestines?

Abstract

To prevent thromboses after surgery, patients have until now had to inject themselves daily with heparin. For stroke prophylaxis in atrial fibrillation, patients take vitamin K antagonists of the coumarin type, which have a narrow therapeutic window and whose dosage must be regularly monitored. In order to improve the standard of therapy in thromboembolic diseases such as deep-vein thrombosis, pulmonary embolism, and stroke in atrial fibrillation, intensive research has been carried out over the last decade in the search for new, orally active thrombin and factor Xa inhibitors. A number of these compounds are already on the market or are in advanced clinical development; they could revolutionize the anticoagulant market.

Dynamic affinity chromatography in the separation of sulfated lignins binding to thrombin

“…An overwhelming number of orthosteric inhibitors of thrombin and factor Xa have been designed [6,14,15] and our discovery that sulfated LMWLs utilized a radically different mechanism [3] suggested a strong possibility of uncovering potent oligomeric allosteric anticoagulants.…”

Anticoagulant therapy

“…highly effective inhibition). (2) Considerable selectivity toward the target enzyme compared with other related serine proteases (at present this requirement is being reconsidered, as double inhibitors of thrombin and factor Xa are being developed [66]; it is, however, still indispensable that new inhibitors be selective with regard to coagulation factors, as compared with such digestive serine proteases as trypsin or chymotrypsin).…”

“…A large number of reviews describing the development of low molecular weight thrombin and factor Xa inhibitors have been published in scientific literature to date [38,49,66,67]. In reality, however, only a small number of these drugs have been approved for clinical practice by now: argatroban (a direct thrombin inhibitor for intravenous administration) [57,68,69], dabigatran etexilate (a direct oral thrombin inhibitor) [70], as well as a number of Xa factor inhibitors: fondaparinux and indraparinux (in clinical trials) that work in complex with !GIII (for intravenous administration) [71][72][73][74], and rivaroxaban (a direct oral factor Xa inhibitor) [75,76].…”

Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation

“…These diseases, collectively, are a leading cause of mortality and morbidity, particularly among elderly patients [8]. Thrombin inhibition, therefore, provides a validated approach for anticoagulation therapy; and over the past decades, there have been significant efforts to discover small molecules that act as direct thrombin inhibitors [9][10][11]. These efforts have resulted in the introduction of dabigatran, a direct thrombin inhibitor, into the market as a prophylaxis to reduce the risk of thromboembolism [12].…”