Antithrombotic effects of a synthetic inhibitor of activated factor X, JTV-803, in animals.
JTV-803, 4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate, at > or = 0.1 mg/kg/h inhibited the increase in plasma thrombin-antithrombin III complex in response to continuous infusion of thromboplastin in rats. JTV-803 inhibited thrombus formation in an arteriovenous shunt model by intravenous infusion at > or = 0.3 mg/kg/h and prolonged the occlusion time of photochemically induced arterial thrombus in the middle cerebral artery at >1.5 mg/kg/0.5 h. Activated partial thromboplastin time was prolonged at 10 mg/kg/h. Intravenous administration of JTV-803 prolonged bleeding time at 30 mg/kg/h, a dose 10-100 times higher than the dose that inhibited thrombus formation. Compared with thrombin inhibitor, JTV-803 had less of an effect on the bleeding time. In the arteriovenous shunt model in cynomolgus monkey, JTV-803 prolonged the occlusion time when administered by continuous infusion at 0.3 mg/kg/h or orally at 10 mg/kg. These results suggest that the human factor Xa inhibitor JTV-803 is an orally active anticoagulant that does not affect bleeding time and is useful for the prevention of thrombus.
Hayashi
M
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Osaka 569-1125, Takatsuki, Japan.
Matsuo
A
A
Nakamoto
H
H
Aisaka
K
K
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D000990:Antithrombin III / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives; D001760:Bleeding Time; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology / Q000627:therapeutic use; D007546:Isoquinolines / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D010314:Partial Thromboplastin Time; D010447:Peptide Hydrolases / Q000097:blood / Q000187:drug effects*; D010875:Pipecolic Acids / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy
C442639:4-((2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D007546:Isoquinolines; D010875:Pipecolic Acids; D010880:Piperidines; D011725:Pyridines; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D001120:Arginine; D010447:Peptide Hydrolases; C031942:argatroban