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Selective tissue factor/factor VIIa Inhibitor, ER-410660, and its prodrug, E5539, have anti-venous and anti-arterial

Tadashi Nagakura1, Kimiyo Tabata, Kazunobu Kira

  • 1Eisai Company, Ltd., Tsukuba Research Laboratories, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.

Thrombosis Research
|July 6, 2013
PubMed
Abstract

Insights

Selective tissue factor/factor VIIa inhibitors, like ER-410660, show promise as novel anticoagulants. These compounds may reduce thrombosis risk with a lower likelihood of causing bleeding complications.

Area of Science:

  • Pharmacology
  • Hematology
  • Biochemistry

Background:

  • Current anticoagulants often target common coagulation pathways, increasing bleeding risk.
  • Tissue factor (TF)/factor VIIa complex specifically initiates the extrinsic pathway and is linked to thrombosis.

Purpose of the Study:

  • To assess the anticoagulant properties and bleeding risk of TF/VIIa inhibitors ER-410660 and its prodrug E5539.
  • To evaluate the in vivo efficacy and safety of these inhibitors in thrombosis and bleeding models.

Main Methods:

  • In vitro enzyme inhibition and plasma clotting assays for ER-410660 and E5539.
  • In vivo studies using rhesus monkey and rat models for thrombosis (TF-induced, stasis-induced, arterial) and bleeding (rat tail-cut).

Main Results:

  • ER-410660 selectively inhibited the extrinsic pathway, reduced thrombin generation, and decreased venous and arterial thrombosis in vivo.
  • ER-410660 doubled bleeding time at higher doses, suggesting a potentially improved safety profile.
  • The prodrug E5539 also demonstrated dose-dependent inhibition of TF-induced thrombin generation.

Conclusions:

  • Selective TF/VIIa inhibitors offer a potential new class of anticoagulants.
  • These inhibitors may provide therapeutic benefits with a reduced propensity for bleeding complications.
Keywords:
AnticoagulantE5539ER-410660Factor VIIaThrombosisTissue factor

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