Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1

Thrombosis is a major cause of mortality in the industrialized world. There fore, 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 protbrombin activation. We repo rt a series of novel biaryl-substituted isoxazoline derivatives in which th e biaryl moiety was designed to interact with the S-4 aryl-binding domain o f the FXa active site. Several of the compounds herein have low nanomolar a ffinity for FXa, have good in vitro selectivity for FXa, and show potent an tithrombotic efficacy in vivo, The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, resp ectively, and ID50's ranging from 0.15 to 0.26 mu mol/kg/h in the rabbit ar terio-venous thrombosis model.