Alexander Straub

In vitro and in vivo studies of the novel antithrombotic agent BAY 59‐7939—an oral, direct Factor Xa inhibitor

Summary.  BAY 59‐7939 is an oral, direct Factor Xa (FXa) inhibitor in development for the prevention and treatment of arterial and venous thrombosis. BAY 59‐7939 competitively inhibits human FXa (Ki 0.4 nm) with > 10 000‐fold greater selectivity than for other serine proteases; it also inhibited prothrombinase activity (IC50 2.1 nm). BAY 59‐7939 inhibited endogenous FXa more potently in human and rabbit plasma (IC50 21 nm) than rat plasma (IC50 290 nm). It demonstrated anticoagulant effects in human plasma, doubling prothrombin time (PT) and activated partial thromboplastin time at 0.23 and 0.69 µm, respectively. In vivo, BAY 59‐7939 reduced venous thrombosis (fibrin‐rich, platelet‐poor thrombi) dose dependently (ED50 0.1 mg kg−1 i.v.) in a rat venous stasis model. BAY 59‐7939 reduced arterial (fibrin‐ and platelet‐rich) thrombus formation in an arteriovenous (AV) shunt in rats (ED50 5.0 mg kg−1 p.o.) and rabbits (ED50 0.6 mg kg−1 p.o.). Slight inhibition of FXa (32% at ED50) reduced thrombus formation in the venous model; to affect arterial thrombosis in the rat and rabbit, stronger inhibition of FXa (74%, 92% at ED50) was required. Calculated plasma levels in rabbits at the ED50 were 14‐fold lower than in the rat AV shunt model, correlating with the 14‐fold lower IC50 of FXa inhibition in rabbit compared with rat plasma; this may suggest a correlation between FXa inhibition and antithrombotic activity. Bleeding times in rats and rabbits were not significantly affected at antithrombotic doses (3 mg kg−1 p.o., AV shunt). Based on these results, BAY 59‐7939 was selected for clinical development.

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

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 structure–activity 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.