Advances in the development of thrombin inhibitors.
Thromboembolic diseases are a major cause of morbidity and mortality, particularly in the Western world, which has stimulated enormous research efforts by the pharmaceutical industry to introduce new antithrombotic therapies. One strategy is the development of direct inhibitors of the serine protease thrombin, which holds a central position in the final steps of the blood 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 heparin, warfarin and aspirin are ineffective or associated with side effects. However, for use in prophylaxis of thrombotic diseases such inhibitors should be orally available, must be safe to avoid bleeding complications and should have an appropriate half-life, allowing once or twice daily dosing to maintain adequate antithrombotically effective blood levels. Details of several new and potent thrombin inhibitors have been published during the last years. For some of them oral bioavailability is claimed and they are effective in in vitro coagulation assays. However, most of them showed only limited efficacy in animal studies with respect to the doses administered. For that reason, effort is concentrated on the evaluation and optimisation of the overall physicochemical characteristics of the inhibitors in order to improve the pharmacokinetics and, thus, the development of promising drug candidates. Nevertheless, only careful clinical studies can give clear answers about the true therapeutical benefit of new developments in this field. This 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.
Steinmetzer
T
T
HaemoSys GmbH, Jena, Germany. T.Steinmetzer@haemosys.de
Hauptmann
J
J
Sturzebecher
J
J
D001120:Arginine / Q000031:analogs & derivatives; D001384:Azetidines; D001596:Benzylamines; D002986:Clinical Trials as Topic; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives; D010446:Peptide Fragments / Q000627:therapeutic use; D010875:Pipecolic Acids / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*
D001384:Azetidines; D001596:Benzylamines; D006629:Hirudins; D010446:Peptide Fragments; D010875:Pipecolic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; C109573:melagatran; D001120:Arginine; D013917:Thrombin; C031942:argatroban; D005998:Glycine; C074619:bivalirudin