Cardiovascular, Endocrine and Metabolic Diseases
Published Online: 15 SEP 2010
Copyright © 2003 by John Wiley & Sons, Inc. All rights reserved.
Burger's Medicinal Chemistry and Drug Discovery
How to Cite
Henry, B. L. and Desai, U. R. 2010. Anticoagulants. Burger's Medicinal Chemistry and Drug Discovery. 365–408.
- Published Online: 15 SEP 2010
Thrombotic disorders are a major cause of morbidity and mortality in humans. Examples of thrombotic disorders include pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, acute myocardial infarction, unstable angina, and cerebrovascular thrombosis. Anticoagulants are the mainstay of treatment and prevention of these disorders. The most widely used anticoagulants include unfractionated heparin, low molecular weight heparins and warfarin. Newer agents introduced in the past decade include bivalirudin, fondaparinux, and argatroban. Mechanistically, these anticoagulants either directly inhibit thrombin or indirectly reduce the activity of thrombin and factor Xa. Several new molecules have been recently designed to directly inhibit thrombin and factor Xa with high potency and considerable selectivity, of which dabigatran and rivaroxaban were approved for clinical use in few countries in 2008. Molecules being pursued in clinical trials include AZD0837, LB-30870, otamixaban, apixaban, YM-150, and others. Ximelagatran, which was introduced in 2004 as a direct thrombin inhibitor, was taken off the market within 20 months due to significant hepatotoxicity. Indirect anticoagulants utilize the antithrombin-mediated conformational activation and bridging mechanisms for inhibiting coagulation enzymes. Among the indirect anticoagulants that are currently being investigated in clinical trials are a biotinylated idraparinux and SR123781. Over the last two decades, major conceptual strides have been made including the design of the first anticoagulant based solely on factor Xa inhibition (fondaparinux) and the establishment of the paradigm that anticoagulation is possible without frequent laboratory monitoring (ximelagatran). Current work attempts to establish other concepts such as the dual inhibition of free and clot-bound thrombin by a heparin-based molecule (ORG42675) and the applicability of neutral P1-group containing active site-directed molecules as effective inhibitors of coagulation enzymes (rivaroxaban). To date, no molecule has been designed that satisfies all the properties of an ideal anticoagulant including a broad therapeutic window, absence of bleeding risk, no requirement for frequent coagulation monitoring, oral bioavailability, availability of an effective antidote, lack of hepatoxicity and absence other adverse effects. Yet, the newer agents are likely to be more attractive than the heparin- and coumarin-based therapy. In this chapter, we review the structure, design, and mechanism of action of clinically used and new potential anticoagulants. Special emphasis is placed on the molecular interaction of anticoagulants with their targets.
- coagulation cascade inhibitors;
- direct factor Xa inhibitors;
- direct thrombin inhibitors;
- low molecular weight heparin;
- mechanism of action;
- vitamin K antagonists