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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Chemical References |
- 1-(N-(2-(Amidinoaminooxy)ethyl)amino)carbonylmethyl-6-methyl-3-(2,2-difluoro-2-phenylethylamino)pyrazinone
- Anticoagulants
- Cytochrome P-450 CYP3A Inhibitors
- Fibrinolytic Agents
- Guanidines
- Pyrazines
- Recombinant Proteins
- Cytochrome P-450 CYP3A
- CYP3A4 protein, human
- Thrombin
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Topics |
- Amino Acid Motifs
- Animals
- Anticoagulants
(chemical synthesis, pharmacokinetics, pharmacology)
- Blood Pressure
(drug effects)
- Caco-2 Cells
- Crystallography, X-Ray
- Cytochrome P-450 CYP3A
- Cytochrome P-450 CYP3A Inhibitors
- Dogs
- Double-Blind Method
- Electrocardiography
- Female
- Fibrinolytic Agents
(chemical synthesis, pharmacokinetics, pharmacology)
- Guanidines
(chemical synthesis, pharmacokinetics, pharmacology)
- Guinea Pigs
- Heart Rate
(drug effects)
- Hemodynamics
(drug effects)
- Humans
- In Vitro Techniques
- Male
- Microsomes, Liver
(metabolism)
- Models, Molecular
- Pyrazines
(chemical synthesis, pharmacokinetics, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Recombinant Proteins
(antagonists & inhibitors)
- Structure-Activity Relationship
- Thrombin
(antagonists & inhibitors, chemistry)
- Venous Thrombosis
(blood, drug therapy)
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