Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2

Intravascular clot formation is an important factor in a number of cardiova scular diseases, Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the i nhibition 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 pos ition of the isoxazoline ring led to SK549 which showed subnanomolar FXa po tency (K-i 0.52 nM). SK549 shows good selectivity for FXa compared to throm bin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.