MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
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| Abstract |
The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
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| Authors | Nigel J Liverton, Steven S Carroll, Jillian Dimuzio, Christine Fandozzi, Donald J Graham, Daria Hazuda, M Katherine Holloway, Steven W Ludmerer, John A McCauley, Charles J McIntyre, David B Olsen, Michael T Rudd, Mark Stahlhut, Joseph P Vacca |
| Journal | Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 54 Issue 1 Pg. 305-11 (Jan 2010) ISSN: 1098-6596 [Electronic] United States |
| PMID | 19841155 (Publication Type: Journal Article) |
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