COMPARISON OF THE ANTICOAGULANT AND ANTITHROMBOTIC EFFECTS OF YM-75466, A NOVEL ORALLY-ACTIVE FACTOR XA INHIBITOR, AND WARFARIN IN MICE

The anticoagulant and antithrombotic effects of YM-75466 (N-[4-[(1-ace timidoyl-4-piperidyl) ]phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamo yl 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 effec ts of YM-75466 occurred I hr after administration while the peak of wa rfarin activity occurred 18 hr after administration. At each peak, bot h YM-75466 and warfarin prolonged coagulation time dose-dependently, T he dose response curve of warfarin for prothrombin time was steeper th an that of YM-75466. In a thromboplastin-induced thromboembolism model , administration of 30 mg/kg YM-75466 or 3 mg/kg warfarin significantl y improved the lethality ratio. In blood loss studies, YM-75466 did no t increase blood loss from the tail even at 30 mg/kg, while warfarin m arkedly increased blood loss at 3 mg/kg. Agents that interfere with wa rfarin action did not interfere with YM-75466 action. In conclusion, t his study shows that YM-75466 has advantages over warfarin: i) rapid o nset of anticoagulant activity, ii) wide therapeutic range, iii) littl e effect on bleeding and iv) lack of drug interaction with agents that interfere with warfarin. These results suggest that YM-75466 may be p romising as a novel oral anticoagulant agent.