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 recepto rs on platelets and various cell types. A safe and effective inhibitor of thrombin active site could be a useful tool in the treatment of ve nous 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 widel y sought goal in the pharmaceutical industry. However, this search has thus far proved elusive. Criteria for a pharmaceutically acceptable t hrombin inhibitor include high and reproducible bioavailability, selec tivity, and a long duration of action. The profile of currently resear ched thrombin active site inhibitors is discussed in relation to these goals.