Antiviral efficacy of NS3‐serine protease inhibitor BILN‐2061 in patients with chronic genotype 2 and 3 hepatitis C†‡

Reiser, Markus; Hinrichsen, Holger; Benhamou, Yves; Reesink, H. W.; Wedemeyer, Heiner; Avendaño, Cristina; Riba, N.; Yong, Chan‐Loi; Nehmiz, Gerhard; Steinmann, Gerhard

doi:10.1002/hep.20612

Cited by 168 publications

(100 citation statements)

References 9 publications

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“…The first clinical proof of concept for an HCV direct antiviral inhibitor was shown for BILN-2061 ( Fig. 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.…”

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

144

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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

144

View full text Add to dashboard Cite

show abstract

“…Inhibitors of the NS3/4A protease have been the most extensively studied direct antivirals to date. BILN 2061 (ciluprevir) was the first NS3/4A protease inhibitor to enter clinical trials; however, trials were halted due to cardiac toxicity in rhesus monkeys (Reiser et al, 2005). Ciluprevir has opened the door to future trials with NS3/4A protease inhibitors.…”

Section: Protease Inhibitorsmentioning

confidence: 99%

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

Tong

Wang

2012

J. Zhejiang Univ. Sci. B

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Abstract:Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-α (PEG-IFN α) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs.

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“…BILN 2061 was the first HCV protease inhibitor to enter clinical trials, and early results were highly promishing showing a rapid and significant decline in plasma HCV RNA virus load in all treated patients infected with HCV genotype 1 (Lamarre et al, 2003). Unfortunately, further development of the compound had to be stopped due to cardiac toxicity (Reiser et al, 2005). In recent studies, a comparative analysis of the ability of two potent macrocyclic inhibitors of NS3/4A protease (TMC435350 and TMC380765, Table 2) to inhibit HCV RNA replication and to restore IFNβ production was carried out using a genome length NNeoC-5B/2-3 cell replicon system (Liang et al, 2008).…”

Section: Hcv Targeting By New Chemical Entitiesmentioning

confidence: 99%

Cellular models for the screening and development of anti-hepatitis C virus agents

Gondeau

Pichard-Garcia

Maurel

2009

Pharmacology & Therapeutics

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Investigations on the biology of hepatitis C virus (HCV) have been hampered by the lack of small animal models. Efforts have therefore been directed to designing practical and robust cellular models of human origin able to support HCV replication and production in a reproducible, reliable and consistent manner. Many different models based on different forms of virions and hepatoma or other cell types have been described including virus-like particles, pseudotyped particles, subgenomic and full length replicons, virion productive replicons, immortalised hepatocytes, fetal and adult primary human hepatocytes. This review focuses on these different cellular models, their advantages and disadvantages at the biological and experimental levels, and their respective use for evaluating the effect of antiviral molecules on different steps of HCV biology including virus entry, replication, particles generation and excretion, as well as on the modulation by the virus of the host cell response to infection.

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Antiviral efficacy of NS3‐serine protease inhibitor BILN‐2061 in patients with chronic genotype 2 and 3 hepatitis C†‡

Cited by 168 publications

References 9 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

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

Cellular models for the screening and development of anti-hepatitis C virus agents

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