RPR120844, a Novel, Specific Inhibitor of Coagulation Factor Xa Inhibits Venous Thrombosis in the Rabbit

Summary

The in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation 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), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, 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 μg/kg/min. At doses of 10, 30 and 100 μg/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 were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 ± 0.3, 1.5 ± 0.9 and 2.4 ± 0.6 μM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.

^* Currently at Eli Lilly & Co

• References

• 1 Weitz I J, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound throm-bin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by anti-thrombin III-independent inhibitors. J Clin Invest 1990; 86 (August) 385-91.
• 2 Prager NA, Abendschein DR, McKenzie CR, Eisenberg PR. Role of throm-bin compared with factor Xa in the procoagulant activity of whole blood clots. Circulation 1995; 92: 962-7.
• 3 Eisenberg PR, Siegel JE, Abdenschein DR, Miletich JP. Importance of factor Xa in determining the procoagulant activity of whole-blood clots. J Clin Invest 1993; 91 (May) 1877-83.
• 4 McKenzie CR, Abendschein DR, Eisenberg PR. Sustained inhibition of whole-blood clot procoagulant activity by inhibition of thrombuS-associated factor Xa. Arterioscler Thromb Vasc Biol 1996; 16: 1285-91.
• 5 Schaffer LW, Davidson JT, Vlasuk GP, Dunwiddie CT, Sigel PKS. Selective factor Xa inhibition by recombinant antistasin prevents vascular graft thrombosis in baboons. Arteriosclerosis and Thrombosis 1992; 12: 879-85.
• 6 Nicolini FA, Lee P, Malycky JL, Lefkovits J, Kottke-Marchant K, Plow EF. Selective inhbition of factor Xa during thrombolytic therapy markedly improves coronary artery patency in a canine model of coronary thrombosis. Blood Coagul Fibrin 1996; 7: 39-48.
• 7 Vlasuk GP, Ramjit D, Fujita T, Dunwiddie CT, Nutt EM, Smith DE. Comparison of the in vivo anticoagulant properties of standard heparin and the highly selective factor Xa inhibitors antistasin and Tick Anticoagulant Peptide (TAP) in a rabbit model of venous thrombosis. Thromb Haemost 1991; 65: 257-62.
• 8 Rebello SS, Blank HS, Rote WE, Vlasuk GP, Lucchesi BR. Antithrombotic efficacy of a recombinant nematode anticoagulant peptide (rNAP5) in canine models of thrombosis after single subcutaneous administration. J Pharm Exp Ther 1997; 283: 91-9.
• 9 Hara T, Yokoyama A, Ishihara H, Yokoyama Y, Nagahara T, Iwamoto M. DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa. Thromb Haemost 1994; 71: 314-9.
• 10 Herbert JM, Bernat A, Dol R, Herault JP, Crepon B, Lormeau JC. DX 9065, a novel, synthetic, selective and orally active inhibitor of factor Xa: In vitro and in vivo studies. J Pharm Exp Ther 1996; 276: 1030-8.
• 11 Herbert JM, Petitou M, Lormeau JC, Cariou R, Necciari J, Magnani HN. SR 90107A/Org 31540, a novel anti-factor Xa antithrombotic agent. Cardiovascular Drug Reviews 1997; 15 (01) 1-26.
• 12 Sato K, Kawasaki T, Hisamichi N, Taniuchi Y, Hirayama F, Koshio H. Antithrombotic effects of YM-60828, a newly synthesized factor Xa inhibitor, in rat thrombosis models and its effects on bleeding time. Brit J Pharmacol 1998; 123: 92-6.
• 13 National Research Council. Guide for the care and use of laboratory animals. Washington, D.C: National Academy Press; 1996
• 14 Kotze HF, Lamprecht S, Badenhorst PN, Roodt JP, vanWyk V. Transient interruption of arterial thrombosis by inhibition of factor Xa results in long-term antithrombotic effects. Thromb Haemost 1997; 77: 1137-42.
• 15 Lyle EM, Fujita T, Conner MW, Connolly TM, Vlasuk GP, Lynch Jr. JL. Effect of inhibitors of factor Xa or platelet adhesion, heparin, and aspirin on platelet deposition in an atherosclerotic rabbit model of angioplasty injury. J Pharmacol Toxicol Meth 1995; 33: 53-61.