PHARMACOLOGICAL CHARACTERIZATION OF AN ORAL DIRECT THROMBIN INHIBITOR, MCC-977: HIGH THROMBIN SPECIFICITY AND LOW HEMORRHAGIC PROFILE
Abstract number: P-T-643
Nakajima1 M., Suga1 M., Sugawara1 K., Katsu1 M., Yuki1 S., Anabuki1 J., Yamamoto1 T., Abe1 Y., Kitada1 Y.
1Pharmaceuticals Research Unit, Mitsubishi Pharma Corporation, Yokohama, Japan
How-to-cite Nakajima M, Suga M, Sugawara K, Katsu M, Yuki S, Anabuki J, Yamamoto T, Abe Y, Kitada Y. PHARMACOLOGICAL CHARACTERIZATION OF AN ORAL DIRECT THROMBIN INHIBITOR, MCC-977: HIGH THROMBIN SPECIFICITY AND LOW HEMORRHAGIC PROFILE. J Thromb Haemost 2007; 5 Supplement 2: P-T-643
Abstract
Introduction: A lower hemorrhagic risk has been required for anti-thrombotic therapy. We examined the property of enzymatic inhibition, the anti-thrombotic and the hemorrhagic effect of MCC-977 (MC), in comparison with melagatran (Mel)/ximelagatran.
Methods: The enzymatic inhibition was evaluated in terms of serine proteases in coagulation system, including trypsin and prothrombinase-bound Xa. The Thrombogram system was used for the thrombin generation analysis in rat plasma. The compounds were orally administrated in a fasted condition.
For the evaluation of anti-thrombotic effect, the thrombus formation was induced by insertion of stainless coil into the inferior vena cava in rats. The hemorrhagic time prolongation was evaluated in a rat tail transection bleeding time model.
Results: MC had Ki values for human thrombin of 9.6nM and trypsin of 4.4 muM. Mel had 6.4 and 8.9 nM, indicating superior selectivity against thrombin of MC. Mel inhibited prothrombinase-bound Xa activity with IC50 of 75nM, but not MC (>3 muM). Thrombin generation analysis showed that the inhibitory effect on endogenous thrombin potential was equivalent, but only Mel prolonged time to peak, indicating a different effect on the thrombin generation between MC and Mel.
MC at 9.1 mg/kg significantly inhibited thrombus formation to 65% of the control. MC did not significantly prolong the bleeding time even at 300 mg/kg. Ximelagatran at 3 mg/kg inhibited thrombus formation and at 29 mg/kg prolonged the hemorrhagic time. MC had lower hemorrhagic risk, compared to ximelagatran.
Conclusions: MC is a highly specific thrombin inhibitor and shows low hemorrhagic effect, suggesting its usefulness for anti-thrombotic therapy.
