Background
Boceprevir is a potent and selective inhibitor of hepatitis C virus (HCV) protease NS3 with Ki value of 14 nM [1].
HCV is a type of RNA virus and infects about 300 million people worldwide. As a serine protease of HCV, NS3 plays an important role in the replication process of HCV when the virus enters the host cell. NS3 processes the polyprotein translated from the virus RNA genome and promotes the maturation of the virus. NS3 is also found to restore the interferon-sensitive signaling pathway. Due to these features, NS3 is thought to be the appropriate target for the therapy of antivirus. The SAR studies led to the discovery of boceprevir (also named as SCH 503034). Boceprevir has a ketoamide group, it binds NS3 and forms a covalent and reversible adduct with the active site serine [1, 2 and 3].
In the cell-based replicon assay using hepatocytes, boceprevir showed improved potency than other derivatives with IC90 value of 350 nM. The selectivity of boceprevir was tested by binding to human neutrophil elastase which had similar structure with NS3. Boceprevir exerted a great selectivity with a HNE/HCV ratio of 2200. It is approximately 15-fold more selective than the corresponding carbamate derivative. In MTS assay, the compound showed no significant cytotoxicity even when its concentration was up to 50 μM [1].
Boceprevir is an orally bioavailable inhibitor of HCV NS3 protease. In rats, oral administration of boceprevir showed AUC value of 1.5 μM?H and bioavailability of 26%. In dogs, boceprevir demonstrated a 30% bioavailability with AUC value of 3.1μM?H at a dose of 3 mg/kg. Boceprevir was also used as a combination therapy with the pegylated interferon (PEG-IFN-α-2B). It was found that the combination showed at least addictive potency compared with each one alone [1, 2].
参考文献:
1.Venkatraman S, Bogen S L, Arasappan A, et al. Discovery of (1 R, 5 S)-N-[3-Amino-1-(cyclobutylmethyl)-2, 3-dioxopropyl]-3-[2 (S)-[[[(1, 1-dimethylethyl) amino] carbonyl] amino]-3, 3-dimethyl-1-oxobutyl]-6, 6-dimethyl-3-azabicyclo [3.1. 0] hexan-2 (S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor: A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection. Journal of medicinal chemistry, 2006, 49(20): 6074-6086.
2.Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon α-2b for genotype 1 nonresponders. Gastroenterology, 2007, 132(4): 1270-1278.
3.Flores M V, Strawbridge J, Ciaramella G, et al. HCV-NS3 inhibitors: determination of their kinetic parameters and mechanism. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, 2009, 1794(10): 1441-1448.
Protocol
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Animal experiment:
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Mice[2] Boceprevir is purchased from MedChem Express. To evaluate the effect of Boceprevir, triple-transgenic mice are induced with Doxycycline (Dox) for 10 days (n=5 per group). On the third day after Dox induction, when plasma Gluc activity reaches its peak, the mice are administered either Boceprevir (100 mg/kg) or DMSO via oral gavage twice daily for 7 days. During this period, blood is collected from the caudal vein daily to detect plasma Gluc activity.
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参考文献:
[1]. Njoroge FG, et al. Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Acc Chem Res. 2008 Jan;41(1):50-9.
[2]. Yao M, et al. Conditional Inducible Triple-Transgenic Mouse Model for Rapid Real-Time Detection of HCV NS3/4A ProteaseActivity. PLoS One. 2016 Mar 4;11(3):e0150894.
[3]. Coilly A, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother. 2012 Nov;56(11):5728-34.
[4]. Berenguer M, et al. New developments in the management of hepatitis C virus infection: focus on boceprevir. Biologics. 2012;6:249-56.
[5]. Burton MJ, et al. Telaprevir and boceprevir in african americans with genotype 1 chronic hepatitis C: implications for patients and providers. South Med J. 2012 Aug;105(8):431-6.
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