Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 4, Pages 1843-1856Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm901802n
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We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K-i = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion tinge 2- rind 3-fold at 0.1 Mind 1.0 mg/kg, iv, respectively, and more than doubled activated clotting tithe and activated partial thromboplastin tithe at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.
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