The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor

Key Points In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first orally administered direct factor Xa inhibitor to be approved for clinical use in the prevention of venous thromboembolism (VTE) after elective hip- or knee-replacement surgery. This article reviews the rationale for its development, the chemical optimization programme that led to its synthesis, its pharmacological characterization and the completed and ongoing clinical studies that underlie its clinical promise. The scientific premise on which a direct factor Xa inhibitor might help to reduce the burden associated with thromboembolic disorders across a range of medical conditions is also presented. Successful early validation studies, conducted with naturally occurring inhibitors of factor Xa, led to the initiation in 1998 of a medicinal chemistry programme to develop oral selective synthetic factor Xa inhibitors. The article details the medicinal chemistry that culminated in the synthesis of rivaroxaban — a molecule that combines both potent, specific inhibition of factor Xa and good oral bioavailability. Rivaroxaban's preclinical profile and subsequent Phase I studies showed that it has many of the characteristics required to address unmet clinical needs: high oral bioavailability, a fast onset/offset of action, dose-dependent pharmacokinetics and pharmacodynamics, few drug–drug or drug–food interactions and, as a result of these, no requirement for routine coagulation monitoring. The extensive clinical-development programme, which will enrol over 65,000 patients, is reviewed and covers the four completed studies for VTE prevention after elective hip or knee replacement; the completed and ongoing VTE treatment studies; and the three ongoing studies for stroke prevention in patients with atrial fibrillation, prevention of recurrent events in acute coronary syndromes and VTE prevention in patients with an acute medical illness. In closing, the article provides an overview of other oral anticoagulants in development and discusses their clinical potential with a view to the impact they may have in improving outcomes for patients affected by thromboembolic disorders. The anticoagulant rivaroxaban is the first approved direct inhibitor of the serine protease factor Xa. This article presents the history of rivaroxaban's development, from its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical developme