Dabigatran Etexilate : Pharmacology of the New, Oral Direct Thrombin Inhibitor

Dabigatran etexilate, the oral direct thrombin inhibitor, has now been successfully introduced into the clinic for the reduction of stroke in patients with atrial fibrillation in many countries around the world. In addition, it has found a role in 83 countries world wide in the prevention of venous thromboembolism after orthopedic hip and knee surgery. Dabigatran is a potent, selective and reversible inhibitor of thrombin that was developed by classical medicinal chemistry techniques in the early-mid 1990s. The resulting pharmacological profiling of the compound demonstrated potent anticoagulant and antithrombotic activity in various venous and arterial thrombosis models. In addition, no effect of vitamin K supplementation on its antithrombotic actions was found, in contrast to warfarin. The bleeding profile of this compound was very favorable when measured as safety margin over antithrombotic activity and as compared to warfarin. Dabigatran has also shown efficacy as an antithrombotic agent in models with mechanical heart valves, both in vitro and in vivo. In addition, the effect of thrombin inhibition by dabigatran on PAR1-mediated pathophysiology is also being elucidated. Chronic treatment of dabigatran etexilate in a mouse model of breast cancer has shown beneficial effects in reducing tumor growth progression and metastases. Fibrosis in the lungs induced by bleomycin was also attenuated in an animal model of pulmonary fibrosis after chronic treatment with dabigatran etexilate. In addition, atherosclerosis progression has been reduced in several models of atherosclerosis in mice after treatment of dabigatran for up to 20 weeks. These studies imply that thrombin may be a mediator between coagulation and inflammation and other proliferative processes and its direct inhibition by dabigatran may provide an added benefit, in addition to its antithrombotic and anticoagulant properties.