Kazuo Sato, Yuta Taniuchi, Tomihisa Kawasaki, Fukushi Hirayama, Hiroyuki
Koshio, Yuzo Matsumoto and Yuichi Iizumi
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co.,
Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
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 orally-active 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.
Keywords: YM-75466, Warfarin, Oral anticoagulant, Factor Xa inhibitor