MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
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.
Liverton
Nigel J
NJ
Merck Research Laboratories, Department of Medicinal Chemistry, WP42A-40, West Point, PA 19486, USA. nigel_liverton@merck.com
Carroll
Steven S
SS
Dimuzio
Jillian
J
Fandozzi
Christine
C
Graham
Donald J
DJ
Hazuda
Daria
D
Holloway
M Katherine
MK
Ludmerer
Steven W
SW
McCauley
John A
JA
McIntyre
Charles J
CJ
Olsen
David B
DB
Rudd
Michael T
MT
Stahlhut
Mark
M
Vacca
Joseph P
JP
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002460:Cell Line; D003521:Cyclopropanes; D004285:Dogs; D005838:Genotype; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008253:Macaca mulatta; D002679:Pan troglodytes; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins; D012093:Replicon; D013379:Substrate Specificity; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D003521:Cyclopropanes; D007211:Indoles; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine; D011392:Proline; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C540393:vaniprevir