Discovery and Clinical Evaluation of 1-{N-2-(Amidinoaminooxy)ethylamino}carbonylmethyl-6-methyl-3-2,2-difl uoro-2-phenylethylaminopyrazinone (RWJ-671818), a Thrombin Inhibitor with an Oxyguanidine P1 Motif

摘要

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.