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

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 ID(50) 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 microg/kg/minute and 0. 13 mg/kg i.v. plus 8.7 microg/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 BT(2) 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 microg/kg/minute and 1.1 mg/kg i.v. plus 73.3 microg/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 microg/kg/minute and argatroban at 0.6 mg/kg i.v. plus 40 microg/kg/minute significantly (p<0.05 and p<0.01, respectively) improved the vessel patency in a FeCl(2)-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.

• Authors: J Cho, H Seo, C Yun, B Koo, S Yoshida, T Koga, T Dan, H Kim
• Journal: Thrombosis research (Thromb Res) Vol. 100 Issue 1 Pg. 97-107 (Oct 01 2000) ISSN: 0049-3848 [Print] United States
• PMID: 11053622 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 4-(2-(2-(2-(6-amidino-1-ethylindol-2-yl)ethyl)pyrrolidinylcarbonyl)pyrrolidinyl)-2-amino-4-oxobutanoic acid
• Amidines
• Enzyme Inhibitors
• Ferrous Compounds
• Fibrinolytic Agents
• Pipecolic Acids
• Pyrrolidinones
• Sulfonamides
• Arginine
• Thrombin
• argatroban
• ferrous chloride

Topics

• Administration, Oral
• Amidines (therapeutic use)
• Animals
• Arginine (analogs & derivatives)
• Binding, Competitive
• Bleeding Time
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (therapeutic use)
• Ferrous Compounds
• Fibrinolytic Agents (therapeutic use)
• Humans
• Male
• Molecular Structure
• Partial Thromboplastin Time
• Pipecolic Acids (therapeutic use)
• Protein Binding
• Pyrrolidinones (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sulfonamides
• Thrombin (antagonists & inhibitors)
• Vascular Patency
• Venous Thrombosis (chemically induced, drug therapy)