Comparison of the Anticoagulant and Antithrombotic Effects of YM-75466, a Novel Orally-Active Factor Xa Inhibitor, and Warfarin in Mice.

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  • Sato Kazuo
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Taniuchi Yuta
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Kawasaki Tomihisa
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Hirayama Fukushi
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Koshio Hiroyuki
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Matsumoto Yuzo
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Iizumi Yuichi
    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

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  • Comparison of the Anticoagulant and Ant

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Abstract

The anticoagulant and antithrombotic effects of YM-75466 (N-[4-[(1-acetimidoyl-4-piperidyl) oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl acetic acid monomethanesulfonate), a novel orallyactive factor Xa (FXa) inhibitor, and warfarin were compared in mice. Both agents were orally administered in all studies. In ex vivo studies, the peak effects of YM-75466 occurred 1 hr after administration while the peak of warfarin activity occurred 18 hr after administration. At each peak, both YM-75466 and warfarin prolonged coagulation time dose-dependently. The dose response curve of warfarin for prothrombin time was steeper than that of YM-75466. In a thromboplastin-induced thromboembolism model, administration of 30 mg/kg YM-75466 or 3 mg/kg warfarin significantly improved the lethality ratio. In blood loss studies, YM-75466 did not increase blood loss from the tail even at 30 mg/kg, while warfarin markedly increased blood loss at 3 mg/kg. Agents that interfere with warfarin action did not interfere with YM-75466 action. In conclusion, this study shows that YM-75466 has advantages over warfarin: i) rapid onset of anticoagulant activity, ii) wide therapeutic range, iii) little effect on bleeding and iv) lack of drug interaction with agents that interfere with warfarin. These results suggest that YM-75466 may be promising as a novel oral anticoagulant agent.

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