Structure-based design of thrombin inhibitors

Despite tremendous efforts by the pharmaceutical industry during the last decade, the prevention of thromboembolic events--the major cause of death in industrialized countries--by efficient anticoagulatory therapy has still not been achieved. One therapeutic strategy focuses on competitive small-molecule thrombin inhibitors, which may block undesirable excessive thrombin activity (conversion of fibrinogen to fibrin and activation of platelet aggregation) and inactivate thrombin in preformed clots. The design of potent tailor-made thrombin inhibitors has been carried out based on structural data; however, the requirements for a target inhibitor, i.e., good pharmacokinetic and physicochemical profiles, still need to be addressed. This constitutes the main challenge in the current quest for a marketable drug, and is the major focus of the developments described in this review.