Advances in the development of thrombin inhibitors

Thromboembolic diseases are a major cause of morbidity. and mortality, part icularly in the Western world, which has stimulated enormous research effor ts by the pharmaceutical industry to introduce new antithrombotic therapies . One strategy is the development of dirt st inhibitors of the serine prote ase thrombin, which holds a central position in the final steps of the bloo d coagulation cascade and in platelet activation. At present there is only limited clinical use of some parenteral preparations of thrombin inhibitors in acute situations, especially when the common antithrombotic drugs hepar in, warfarin and aspirin are ineffective or associated with side effects. H owever, for use in prophylaxis of thrombotic diseases such inhibitors shoul d be orally available, must be safe to avoid bleeding complications and sho uld have an appropriate half-life, allowing once or twice daily dosing to m aintain adequate antithrombotically effective blood levels. Details of seve ral new and potent thrombin inhibitors have been published during the last years. For some of them oral bioavailability is claimed and they are effect ive in in vitro coagulation assays. However, most of them showed only limit ed efficacy in animal studies with respect to the doses administered. For t hat reason, effort is concentrated on the evaluation and optimisation of th e overall physicochemical characteristics of the inhibitors in order to imp rove the pharmacokinetics and, thus, the development of promising drug cand idates. Nevertheless, only careful clinical studies can give clear answers about the true therapeutical benefit of new developments in this field. Thi s review summarises the current status of direct thrombin inhibitors which are already in clinical use and clinical development and gives an overview on recently published and promising new compounds.