Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease

Perni, Robert B.; Almquist, Susan J.; Byrn, Randal A.; Chandorkar, Gurudatt; Chaturvedi, Pravin; Courtney, Lawrence F.; Decker, Carolin; Dinehart, Kirk; Gates, Cynthia A.; Harbeson, Scott L.; Heiser, Angela D.; Kalkeri, Gururaj; Kolaczkowski, Elaine; Lin, Kai; Luong, Yu-Ping; Rao, B. Govinda; Taylor, W. P.; Thomson, John A.; Tung, Roger D.; Wei, Yang; Kwong, Ann D.; Lin, Chao

doi:10.1128/aac.50.3.899-909.2006

Cited by 359 publications

(268 citation statements)

References 45 publications

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“…1) (16, 23), a rapidly reversible, P1-P3-constrained macrocyclic compound, although its development was subsequently discontinued as a consequence of the cardiac histology seen in monkeys (41). The clinically most advanced inhibitors acting via NS3/4A inhibition, VX-950 (telaprevir) (18,35) and SCH-503034 (boceprevir) (43), are both keto-amide compounds which covalently bind to the active-site serine of the protease in a slowly reversible manner. More recently, a number of compounds structurally related to BILN-2061, including , TMC435350 (49), and BI201335 (28), have progressed to the early stages of clinical evaluation.…”

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confidence: 99%

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

Liverton¹,

Carroll

DiMuzio

et al. 2010

Antimicrob Agents Chemother

143

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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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mentioning

confidence: 99%

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

Liverton¹,

Carroll

DiMuzio

et al. 2010

Antimicrob Agents Chemother

143

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“…The telaprevir formulations were kindly provided by Vertex Pharmaceuticals. A telaprevir suspension was prepared as described previously (Perni et al, 2006) and used in experiments 1 and 2. In the other experiments, a telaprevir suspension was prepared daily as in the tablet formulation (Forestier et al, 2007; Hézode et al, 2009;McHutchison et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

“…Several compounds that inhibit specific stages of the virus life cycle have been clinically evaluated (Manns et al, 2007;Pereira & Jacobson, 2009). Telaprevir is a novel peptidomimetic slow-and tight-binding inhibitor of HCV NS3-4A protease, which was discovered using a structure-based drug design approach (Perni et al, 2006). A rapid decline in viral RNA was observed in CHC patients treated with telaprevir (Reesink et al, 2006) and an increased antiviral effect of a combination of telaprevir and PEG-IFN has been reported (Forestier et al, 2007).…”

mentioning

confidence: 99%

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

Kamiya¹,

Iwao²,

Hiraga

et al. 2010

Journal of General Virology

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A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA +/+ /SCID +/+ mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11-0.17 log 10 h "1 . During the initial phase of treatment, the log 10 reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10 8 virions per day, and this may be comparable to HCV production in the human liver. INTRODUCTIONHepatitis C virus (HCV) is a major cause for concern worldwide. More than 3 % of the world's population is chronically infected with HCV and 3-4 million people are newly infected each year (Wasley & Alter, 2000). Chronic HCV infection is relatively mild and progresses slowly; however, about 20 % of chronic hepatitis C (CHC) carriers progress to serious end-stage liver disease (Lauer & Walker, 2001;Liang et al., 2000;Poynard et al., 2003). The current standard treatment for HCV infection is administration of pegylated alpha interferon (PEG-IFN) in combination with ribavirin (RBV) for 48 weeks. The overall cure rates with this intervention are 40-50 % for patients with genotype 1 and more than 75 % for patients with genotypes 2 and 3 (Fried et al., 2002;Manns et al., 2001). Several compounds that inhibit specific stages of the virus life cycle have been clinically evaluated (Manns et al., 2007;Pereira & Jacobson, 2009). Telaprevir is a novel peptidomimetic slow-and tight-binding inhibitor of HCV NS3-4A protease, which was discovered using a structure-based drug design approach (Perni et al., 2006). A rapid decline in viral RNA was observed in CHC patients treated with telaprevir (Reesink et al., 2006) and an increased antiviral effect of a combination of telaprevir and PEG-IFN has been reported (Forestier et al., 2007). Recent clinical trials of telaprevir in combination with PEG-IFN and RBV have indicated a promising material advance in therapy for CHC patients (Hézode et al., 2009;McHutchison et al., 2009). Firstgeneration HCV-specific agents have been...

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“…The NS3 protease is one of the most attractive targets for developing new therapies against HCV, because of its essential role in viral replication [59,60]. The NS3 inhibitors are divided into two groups, according to different mechanisms of action: covalent and non-covalent inhibitors.…”

Section: Ns3/4a Protease Inhibitorsmentioning

confidence: 99%

Tissue-Based Model of HCV Replication as a Replacement for Animal Models in Drug Testing

Godzik¹

2012

Biomedical Tissue Culture

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Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease

Cited by 359 publications

References 45 publications

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

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

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

Tissue-Based Model of HCV Replication as a Replacement for Animal Models in Drug Testing

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