MK-7009, a Potent and Selective Inhibitor of Hepatitis C Virus NS3/4A Protease
- 1 January 2010
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 54 (1), 305-311
- https://doi.org/10.1128/aac.00677-09
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.Keywords
This publication has 52 references indexed in Scilit:
- Antiviral Activity of MK-4965, a Novel Nonnucleoside Reverse Transcriptase InhibitorAntimicrobial Agents and Chemotherapy, 2009
- Debio 025, a Cyclophilin Binding Molecule, Is Highly Efficient in Clearing Hepatitis C Virus (HCV) Replicon-Containing Cells When Used Alone or in Combination with Specifically Targeted Antiviral Therapy for HCV (STAT-C) InhibitorsAntimicrobial Agents and Chemotherapy, 2009
- Selection and Characterization of Hepatitis C Virus Replicons Dually Resistant to the Polymerase and Protease Inhibitors HCV-796 and Boceprevir (SCH 503034)Antimicrobial Agents and Chemotherapy, 2009
- Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)Antimicrobial Agents and Chemotherapy, 2008
- HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity In Vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virusHepatology, 2008
- Combinations of Cyclophilin Inhibitor NIM811 with Hepatitis C Virus NS3-4A Protease or NS5B Polymerase Inhibitors Enhance Antiviral Activity and Suppress the Emergence of ResistanceAntimicrobial Agents and Chemotherapy, 2008
- Peptidomimetic Therapeutic Agents Targeting the Protease Enzyme of the Human Immunodeficiency Virus and Hepatitis C VirusAccounts of Chemical Research, 2008
- Synergy of a Hepatitis C Virus (HCV) NS4A Antagonist in Combination with HCV Protease and Polymerase InhibitorsAntimicrobial Agents and Chemotherapy, 2008
- Identification and Characterization of 4-Methylbenzyl 4-[(Pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an Orally Bioavailable, Brain Penetrant NR2B Selective N-Methyl-d-Aspartate Receptor AntagonistJournal of Medicinal Chemistry, 2007
- Antiviral interactions of an HCV polymerase inhibitor with an HCV protease inhibitor or interferon in vitroAntiviral Research, 2007