Content area
Full Text
REVIEWS
C A S E H I S TO RY
The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor
Elisabeth Perzborn*, Susanne Roehrig, Alexander Straub, Dagmar Kubitza and
Frank Misselwitz||
Abstract | The activated serine protease factor Xa is a promising target for new anticoagulants. After studies on naturally occurring factor Xa inhibitors indicated that such agents could be effective and safe, research focused on small-molecule direct inhibitors of factor Xa that might address the major clinical need for improved oral anticoagulants. In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first such compound to be approved for clinical use. This article presents the history of rivaroxabans development, from the structureactivity relationship studies that led to its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.
Anticoagulants are used for the prevention and treatment of venous and arterial thromboembolic disorders. Many approaches have been explored in the development of antithrombotic drugs that inhibit enzymes in the coagulation pathways. However, most currently approved drugs for the prevention and treatment of thromboembolic disorders have been on the market for a long time, in some cases for decades. Unfractionated heparin (UFH), which was discovered in 1916 (REF. 1) targets multiple factors in the coagulation cascade2, but has a number of limitations, including a parenteral route of administration, frequent laboratory monitoring of coagulation activity and the risk for patients of developing potentially life-threatening
heparin-induced thrombocytopaenia2,3. Low-molecular-weight heparins (LMWHs), which were developed in the 1980s, promote the inactivation of both thrombin (factor IIa) and, to a greater extent, factor Xa2.
LMWHs have largely replaced UFH owing to their lower risk of causing bleeding, lower levels of binding to plasma proteins and endothelium, good bioavailability, longer half-life and superior pharmacokinetic properties compared with UFH2. However, their use remains limited because of the need for parenteral administration2,
which can be inconvenient, especially in an outpatient setting, with patients needing to be trained to self-inject after discharge, and nurse visits required for those unable to do so4. Both UFH and LMWHs are indirect inhibitors of coagulation, and their activity is mediated by plasma cofactors, principally antithrombin and, to a lesser extent for UFH, heparin cofactor II (REF. 2).
...