From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3

Highly potent and selective substrate analogue factor Xa inhibitors were obtained by incorporation of non-basic or modestly basic P1 residues known from the development of thrombin inhibitors. The modification of the P2 and P3 amino acids strongly influenced the selectivity and provided potent dual factor Xa and thrombin inhibitors without affecting the fibrinolytic enzymes. Several inhibitors demonstrated excellent anticoagulant efficacy in standard clotting assays in human plasma.

Highly potent and selective substrate analogue inhibitors of factor Xa containing weakly basic P1 residues were converted to dual inhibitors of thrombin and factor Xa by simple replacement of the P2 and P3 amino acids. The most potent inhibitors have Ki values in the low nanomolar range for both proteases and possess excellent anticoagulant activity in human plasma.Figure optionsDownload as PowerPoint slide