Challenges in the development of orally bioavailable thrombin active site inhibitors

Activated thrombin plays a central role thrombosis and in hemostasis, both by controlling the coagulation process, and by activating receptors on platelets and various cell types. A safe and effective inhibitor of thrombin active site could be a useful tool in the treatment of venous thrombosis, atrial fibrillation, restenosis, arterial thrombosis, and in the prevention of myocardial infarction. Because of this, the modulation of thrombin by direct, small molecule inhibitors is a widely sought goal in the pharmaceutical industry. However, this search has thus far proved elusive. Criteria for a pharmaceutically acceptable thrombin inhibitor include high and reproducible bioavailability, selectivity, and a long duration of action. The profile of currently researched thrombin active site inhibitors is discussed in relation to these goals.