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MK-7009, a Potent and Selective Inhibitor of Hepatitis C Virus NS3/4A Protease

2009; American Society for Microbiology; Volume: 54; Issue: 1 Linguagem: Inglês

10.1128/aac.00677-09

1098-6596

Nigel J. Liverton, Steven S. Carroll, Jillian DiMuzio, Christine Fandozzi, Donald J. Graham, Daria J. Hazuda, M. K. HOLLOWAY, Steven W. Ludmerer, John A. McCauley, Charles McIntyre, David B. Olsen, Michael T. Rudd, Mark W. Stahlhut, Joseph P. Vacca,

HIV/AIDS drug development and treatment

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.