Characteristics of the hemostatic action of KFA-1411, an inhibitor of coagulation factor Xa (FXa), in humans and various animals

Kiyoto Hara, Toshiki Honma, Akane Matsuzawa, Atsushi Matsuzawa, Masahiko Uchida, Takashi Koizumi, Satoshi Akahane, Masami Kojima

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4-yl] phenyl]carbamoylmethyl]aminomethyl]phenoxy-acetic acid monosulfonate·dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans.

Original languageEnglish
Pages (from-to)25-34
Number of pages10
JournalJournal of Toxicological Sciences
Volume28
Issue number1
DOIs
Publication statusPublished - 2003 Feb
Externally publishedYes

Keywords

  • Coagulation
  • Factor-Xa
  • Factor-Xa inhibitor
  • Hemostatic action
  • Platelet
  • Thrombin

ASJC Scopus subject areas

  • Toxicology

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