The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor, in rat models of venous and arterial thrombosis.
The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis. After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50, (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively. In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P < 0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively. The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times. These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.
Cho
J H
JH
C&C Research Laboratories, Hwasung-goon, Kyunggi-do, Republic of Korea. thromres_cho@yahoo.com
Yun
C H
CH
Seo
H S
HS
Koga
T
T
Dan
T
T
Koo
B A
BA
Kim
H Y
HY
D000284:Administration, Oral; D000578:Amidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000517:prevention & control; D017985:Dalteparin / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D010875:Pipecolic Acids / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000517:prevention & control; D014859:Warfarin / Q000627:therapeutic use
C459443:4-((1-(2-(2-(2-(6-amidino-1-ethylindol-2-yl)ethyl)pyrrolidinyl)-2-oxoethyl)-2-oxoazaperhydroepin-3-yl)amino)butanoic acid; D000578:Amidines; D001381:Azepines; D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D013449:Sulfonamides; D014859:Warfarin; D001120:Arginine; D013917:Thrombin; C031942:argatroban; D017985:Dalteparin