A NOVEL FACTOR XA INHIBITOR - STRUCTURE-ACTIVITY-RELATIONSHIPS AND SELECTIVITY BETWEEN FACTOR XA AND THROMBIN

A series of 3-amidinoaryl-2-[4-[[(3S)-3-pyrrolidinyl]oxy]phenyl] propanoic acids have been investigated for development of a novel factor Xa inhibitor, possessing a potent inhibitory activity for factor Xa and a selectivity for factor Xa compared to thrombin. In order to study the structure-activity relationships and the selectivity, models of factor Xa complexes formed with the inhibitors were constructed on the basis of X-ray crystallographic data of a trypsin-inhibitor complex. The models showed that the binding mode of the inhibitors to the S1 pocket of the enzyme accounted for the structure- activity relationships and that the difference between Gln192 of factor Xa and Glu192 of thrombin had a key role in the selectivity. © 1993 Academic Press, Inc.