Discovery and clinical evaluation of 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-[2,2-difluoro-2-phenylethylamino]pyrazinone (RWJ-671818), a thrombin inhibitor with an oxyguanidine P1 motif.
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| Abstract |
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 time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time 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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| Authors | Tianbao Lu, Thomas Markotan, Shelley K Ballentine, Edward C Giardino, John Spurlino, Carl S Crysler, Kathryn Brown, Bruce E Maryanoff, Bruce E Tomczuk, Bruce P Damiano, Umesh Shukla, David End, Patricia Andrade-Gordon, Roger F Bone, Mark R Player |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 4 Pg. 1843-56 (Feb 25 2010) ISSN: 1520-4804 [Electronic] United States |
| PMID | 20102150 (Publication Type: Journal Article, Randomized Controlled Trial) |
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