Approaches in anticoagulation: rationales for target positioning.
Heparin and warfarin are the most widely used anticoagulants for the prophylaxis and treatment of thrombus-based diseases. These anticoagulants, however, have well-known clinical limitations, such as a slow onset of action and a narrow therapeutic window. An ideal small-molecule non-peptide inhibitor should have an immediate onset of action, oral bioavailability and an improved therapeutic action and side-effect profile, compared to established therapies. In this review, the current concepts and hypotheses of the numerous anticoagulant approaches are analyzed and evaluated, with emphasis on animal models, genetic disorders and compound profiling. Selected factors of the coagulation cascade and modulators of endogenous fibrinolysis are examined to determine if they represent promising drug targets in antithrombotic therapy.
Wieland
Heike A
HA
Aventis Pharma Deutschland GmbH, Disease Group of Thrombotic and Degenerative Joint Diseases, Industriepark Höchst, 65926 Frankfurt, Germany. heike.wieland@aventis.com
Laux
Volker
V
Kozian
Detlef
D
Lorenz
Martin
M
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors; D016503:Drug Delivery Systems; D015949:Factor IXa / Q000037:antagonists & inhibitors; D015942:Factor VIIa / Q000037:antagonists & inhibitors; D026122:Factor XIIIa / Q000037:antagonists & inhibitors; D065427:Factor Xa Inhibitors; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013925:Thromboplastin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control*
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D013925:Thromboplastin; D026122:Factor XIIIa; D025901:Carboxypeptidase B2; D015942:Factor VIIa; D015949:Factor IXa