Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors. 2

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency ( K i 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.