title: Selective tissue factor/factor VIIa Inhibitor, ER-410660, and its prodrug, E5539, have anti-venous and anti-arterial thrombotic effects with a low risk of bleeding.
abstract: BACKGROUND
  Many anticoagulant drugs target factors common to both the intrinsic and extrinsic coagulation pathways, which may lead to bleeding complications. Since the tissue factor (TF)/factor VIIa complex is associated with thrombosis onset and specifically activates the extrinsic coagulation pathway, compounds that inhibit this complex may provide therapeutic and/or prophylactic benefits with a decreased risk of bleeding.
  
  
  METHODS
  The in vitro enzyme profile and anticoagulation selectivity of the TF/VIIa complex inhibitor, ER-410660, and its prodrug E5539 were assessed using enzyme inhibitory and plasma clotting assays. In vivo effects of ER-410660 and E5539 were determined using a TF-induced, thrombin generation rhesus monkey model; a stasis-induced, venous thrombosis rat model; a photochemically induced, arterial thrombosis rat model; and a rat tail-cut bleeding model.
  
  
  RESULTS
  ER-410660 selectively prolonged prothrombin time, but had a less potent anticoagulant effect on the intrinsic pathway. It also exhibited a dose-dependent inhibitory effect on thrombin generation caused by TF-injection in the rhesus monkey model. ER-410660 also reduced venous thrombus weights in the TF-administered, stasis-induced, venous thrombosis rat model and prolonged the occlusion time induced by arterial thrombus formation after vascular injury. The compound was capable of doubling the total bleeding time in the rat tail-cut model, albeit with a considerably higher dose compared to the effective dose in the venous and arterial thrombosis models. Moreover, E5539, an orally available ER-410660 prodrug, reduced the thrombin-anti-thrombin complex levels, induced by TF-injection, in a dose-dependent manner.
  
  
  CONCLUSIONS
  Selective TF/VIIa inhibitors have potential as novel anticoagulants with a lower propensity for enhancing bleeding.
authors.affiliation: Eisai Company, Ltd., Tsukuba Research Laboratories, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: t-nagakura@hhc.eisai.co.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagakura
authors.forename: Kimiyo
authors.initials: K
authors.lastname: Tabata
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kira
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hirota
authors.forename: Richard
authors.initials: R
authors.lastname: Clark
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Matsuura
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hiyoshi
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D014230:Triazoles / Q000494:pharmacology*; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy
chemical_list: D001550:Benzamidines; C000588885:E5539 compound; C000588884:ER-410660; D005343:Fibrinolytic Agents; D011355:Prodrugs; D014230:Triazoles; D015942:Factor VIIa
keywords: Anticoagulant; E5539; ER-410660; Factor VIIa; Thrombosis; Tissue factor