RPR120844, a novel, specific inhibitor of coagulation factor Xa inhibits venous thrombosis in the rabbit

The in vivo antithrombotic activity of RPR120844, a novel synthetic coagula tion factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), a ctivated partial thromboplastin time (APTT), prothrombin time (PT), inhibit ion of ex vivo fXa activity and plasma drug levels (PDL) were determined. T MI measured at the end of a 50 min infusion, was significantly reduced (p < 0.05 vs saline-treated animals) by RPR120844 at 30 and 100 mu g/kg/min. At doses of 10, 30 and 100 mu g/kg/min: APTT was prolonged by 2.1, 4.2 and 6. 1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL we re determined by measuring anti-fXa activity using an amidolytic assay. Pea k PDL were 0.8 +/- 0.3, 1.5 +/- 0.9 and 2.4 +/- 0.6 mu M, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreat ment Values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily re versible, means of inhibiting thrombus formation.