In vitro and in vivo studies of AT-1362, a newly synthesized and orally active inhibitor of thrombin

Jae hyung Cho, Hyoung sik Seo, Chi ho Yun, Bon am Koo, Shoshin Yoshida, Takaki Koga, Takashi Dan, Hak yeop Kim

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

AT-1362 was found to be a potent, selective, and competitive inhibitor of thrombin, with a Ki value of 6.7 nM. In a rat model of venous thrombosis induced by partial stasis and endothelial disruption, the ID50 values (a dose required to obtain 50% inhibition of thrombus formation over each vehicle group) of AT-1362 and argatroban were 0.03 mg/kg i.v. plus 0.5 μg/kg/minute and 0.13 mg/kg i.v. plus 8.7 μg/kg/minute, respectively, and the antithrombotic effect of AT-1362 without prolongation of bleeding time lasted for 2 hours and disappeared 4 hours after oral administration of 30 mg/kg. In the rat tail transection model, the BT2 values (a dose causing two-fold prolongation of the bleeding time over each vehicle group) of AT-1362 and argatroban were 0.56 mg/kg i.v. plus 9.3 μg/kg/minute and 1.1 mg/kg i.v. plus 73.3 μg/kg/minute, respectively. The reduction of thrombus formation and the prolongation of bleeding time were correlated with an ex vivo activated partial thromboplastin time (APTT) for both drugs. AT-1362 at 0.3 mg/kg i.v. plus 5 μg/kg/minute and argatroban at 0.6 mg/kg i.v. plus 40 μg/kg/minute significantly (p < 0.05 and p < 0.01, respectively) improved the vessel patency in a FeCl2-induced carotid artery thrombosis model in rats. These results suggest that AT-1362 may be a potent antithrombotic agent for the treatment of thrombotic diseases. (C) 2000 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)97-107
Number of pages11
JournalThrombosis Research
Volume100
Issue number1
DOIs
Publication statusPublished - 2000 Oct 1

Keywords

  • AT-1362
  • Antithrombotic effects
  • Argatroban
  • Bleeding time
  • Clotting time

ASJC Scopus subject areas

  • Hematology

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