The Discovery of Dabigatran Etexilate

Abstract

Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g., heparins, low-molecular-weight-heparins) and vitamin K antagonists such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and food- and drug–drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation.

Characterization of Thrombin-Bound Dabigatran Effects on Protease-Activated Receptor-1 Expression and Signaling In Vitro

“…Dabigatran binds directly to the active site of thrombin and inhibits its proteolytic activity, but it leaves the exosites of thrombin unencumbered (van Ryn et al, 2013). These findings suggest that thrombin-bound dabigatran retains the capacity to bind to substrates such as fibrinogen and PARs.…”

“…However, the in vivo physiologic relevance of this effect is not known since the studies were not performed in plasma containing antithrombin. These findings suggest that catalytically inactive thrombin can bind to and modulate PAR1 function in vitro, but whether these effects are translated in vivo is not known, and given the rapid clearance of thrombin and metabolism of dabigatran (Stangier, 2008;van Ryn et al, 2013), it seems unlikely in patients with normal excretion and metabolic processes (Connolly et al, 2013).…”

“…Consequently, major efforts have been made to develop new oral active, direct thrombin inhibitors. Dabigatran is a specific and potent reversible direct thrombin inhibitor that binds to the catalytic site, and not to the exosites of thrombin, and has been approved for the prevention of strokes and blood clots associated with nonvalvular atrial fibrillation (van Ryn et al, 2013). Because dabigatran binds selectively to the active site of thrombin, it does not affect thrombin interaction with fibrinogen via exosite-I (Hogg and Bock, 1997;Sanford and Plosker, 2008;van Ryn et al, 2008).…”

Enhanced Elimination of Dabigatran Through Extracorporeal Methods

“…Extracorporeal removal is a potential consideration for treatment in the setting of dabigatran toxicity. An evaluation of dabigatran's pharmacological profile suggests that extracorporeal removal can expedite its clearance from plasma (Table 2) [1,2,[28][29][30][31][32]. Several authors have provided evidence to support extracorporeal removal as a strategy to manage dabigatran-related hemorrhage [32][33][34].…”

Upstream versus downstream thrombin inhibition

“…After the failure of ximelagatran (terminated because of liver toxicity concerns), dabigatran was the first DTI approved for clinical use in AF patients in 2009 [3]. Dabigatran is a potent and reversible direct inhibitor of the active site of thrombin, thereby inactivating fibrin-bound and free thrombin in vitro [25]. Inhibition of thrombin prevents the conversion of fibrinogen to fibrin but also the positive feedback activation of other coagulation activation, the cross-linking of fibrin monomers, platelet activation, and inhibition of fibrinolysis [26].…”