Direct thrombin inhibitors - a survey of recent developments.
Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.
Schwienhorst
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Department of Molecular Genetics and Preparative Molecular Biology, Institute for Microbiology and Genetics, Grisebachstrasse 8, 37077, Goettingen, Germany. aschwie1@gwdg.de
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001384:Azetidines / Q000009:adverse effects / Q000627:therapeutic use; D001596:Benzylamines / Q000009:adverse effects / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions; D006629:Hirudins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000188:drug therapy; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013927:Thrombosis / Q000188:drug therapy
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D006629:Hirudins; C426686:ximelagatran; D013917:Thrombin