IDENTIFICATION AND INITIAL STRUCTURE-ACTIVITY-RELATIONSHIPS OF A NOVEL CLASS OF NONPEPTIDE INHIBITORS OF BLOOD-COAGULATION FACTOR XA

The discovery and some of the basic structure-activity relationships o f a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized p-alanines, exemp lified by 2a. Docking experiments placing 2a in the active site of Fac tor Xa implied that the Most expeditious route to enhancing in vitro p otency was to modify the group occupying the S3 site of the enzyme. In creasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this s eries. In addition, an enantioselective synthesis of these substituted p-alanines was also developed.