title: Comparison of the anticoagulant and antithrombotic effects of YM-75466, a novel orally-active factor Xa inhibitor, and warfarin in mice.
abstract: The anticoagulant and antithrombotic effects of YM-75466 (N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naph thyl)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.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: Y
authors.initials: Y
authors.lastname: Taniuchi
authors.forename: T
authors.initials: T
authors.lastname: Kawasaki
authors.forename: F
authors.initials: F
authors.lastname: Hirayama
authors.forename: H
authors.initials: H
authors.lastname: Koshio
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Iizumi
mesh_terms: D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006470:Hemorrhage; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010314:Partial Thromboplastin Time; D010672:Phenytoin / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011517:Prothrombin Time; D012293:Rifampin / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013923:Thromboembolism / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control; D013925:Thromboplastin / Q000008:administration & dosage / Q000009:adverse effects; D010837:Vitamin K 1 / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D000927:Anticonvulsants; D000933:Antifibrinolytic Agents; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D010880:Piperidines; D013449:Sulfonamides; C114145:YM 75466; D002220:Carbamazepine; D014859:Warfarin; D010672:Phenytoin; D004917:Erythromycin; D002927:Cimetidine; D010837:Vitamin K 1; D013925:Thromboplastin; D012293:Rifampin