In vitro and in vivo studies of AT-1362, a newly synthesized and orally active inhibitor of thrombin.
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.
Cho
J
J
C&C Research Laboratories, Kyunggi-do, South Korea.
Seo
H
H
Yun
C
C
Koo
B
B
Yoshida
S
S
Koga
T
T
Dan
T
T
Kim
H
H
D000284:Administration, Oral; D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001667:Binding, Competitive; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005296:Ferrous Compounds; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000627:therapeutic use; D011485:Protein Binding; D011760:Pyrrolidinones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014654:Vascular Patency; D020246:Venous Thrombosis / Q000139:chemically induced / Q000188:drug therapy
C417092:4-(2-(2-(2-(6-amidino-1-ethylindol-2-yl)ethyl)pyrrolidinylcarbonyl)pyrrolidinyl)-2-amino-4-oxobutanoic acid; D000578:Amidines; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D011760:Pyrrolidinones; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; C031942:argatroban; C029451:ferrous chloride