Narlaprevir

Narlaprevir
Clinical data
Trade names	Arlansa
Other names	SCH 900518
Routes of; administration	By mouth
ATC code	None;
Legal status
Legal status	Rx-only (RU);
Pharmacokinetic data
Protein binding	86.5–91.4%
Metabolism	Extensive hepatic through oxidation, reduction and N-dealkylation (CYP3A4)
Excretion	Feces (81.1%), urine (3.14%)
Identifiers
	IUPAC name (1R,2S,5S)-3-[(2S)-2-[ [1-(tert-Butylsulfonylmethyl)cyclohexyl]carbamoylamino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxoheptan-3-yl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;
CAS Number	865466-24-6 ;
PubChem CID	11857239 ;
ChemSpider	ID10031710 ;
UNII	2857LA2O07 ;
KEGG	D09644 ;
ChEBI	CHEBI:173104 ;
ChEMBL	ChEMBL1255891 ;
Chemical and physical data
Formula	C36H61N5O7S
Molar mass	707.97 g·mol−1
3D model (JSmol)
	SMILES CCCC[C@H](NC(=O)[C@@H]1[C@@H]2[C@H](CN1C(=O)[C@@H](NC(=O)NC3(CS(=O)(=O)C(C)(C)C)CCCCC3)C(C)(C)C)C2(C)C)C(=O)C(=O)NC4CC4;
	InChI InChI=1S/C36H61N5O7S/c1-10-11-15-24(27(42)30(44)37-22-16-17-22)38-29(43)26-25-23(35(25,8)9)20-41(26)31(45)28(33(2,3)4)39-32(46)40-36(18-13-12-14-19-36)21-49(47,48)34(5,6)7/h22-26,28H,10-21H2,1-9H3,(H,37,44)(H,38,43)(H2,39,40,46)/t23-,24-,25-,26-,28+/m0/s1; Key:RICZEKWVNZFTNZ-LFGITCQGSA-N;

Last updated February 10, 2024

Narlaprevir (trade name Arlansa,^[1] codenamed SCH 900518),^[2] is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus in combination with other antiviral drugs.^[3]^[4]^[5]

Mechanism of action

Narlaprevir is an oral NS3 serine protease inhibitor of hepatitis C virus. It inhibits viral replication in infected host cells.^[2] The mechanism of inhibition involves reversible covalent binding of narlaprevir with NS3 protease active site via the ketoamide functional group.^[2]

Narlaprevir does not bind to human proteases, with the exception of cathepsin B (69% inhibition). Overexpression of cathepsin B is associated with the development of malignancies.^[7]

Usage

Indications

Treatment of chronic hepatitis C virus (HCV) infection genotype 1 in combination with ritonavir, pegylated interferon alfa and ribavirin, in patients older than 18 years with compensated liver disease who are treatment-naïve or have failed dual combination of pegylated interferon alfa and ribavirin. Narlaprevir cannot be used as a single agent.^[1]^[2]^[6]^[8]^[9]

Contraindications

Narlaprevir has some contraindications. In particular:^[1]^[8]

pregnancy or lactation
children up to 18 years of age
severe neutropenia
liver failure
prior treatment with HCV protease inhibitors
lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Efficacy studies

H. Reesink et al. (2009) demonstrated narlaprevir safety and antiviral activity both as a single agent and in dual combination with pegylated interferon alfa-2b.^[10]

X. Tong et al. (2010) demonstrated narlaprevir activity against HCV mutations causing resistance to boceprevir and telaprevir.^[2]

In the year 2016 a large-scale phase III multicenter PIONEER study was completed. Sustained virologic response (SVR) was 89% in treatment-naïve and 70% in treatment-experienced patients 24 weeks after the end of treatment in the narlaprevir group, whereas in the control group SVR was only 59.6% in treatment-naïve and 24.5% in treatment-experienced patients on dual therapy with pegylated interferon alfa and ribavirin. Adding narlaprevir to dual therapy with pegylated interferon alfa and ribavirin did not affect narlaprevir safety profile. A phase I study of narlaprevir pharmacokinetics in combination with ritonavir in patients with compensated cirrhosis was also completed (Liver Meeting AASLD, 13–17 February 2015, San Francisco, California, USA).^[9]^[11]

According to professor I.G. Bakulin, the head of the Department of Hepatology of the Moscow clinical research center and chief gastroenterologist of Moscow government healthcare department, the regulatory approval of narlaprevir has become a major milestone accomplished in the fight against hepatitis C in Russia.^[9]

History

In 2012, the pharmaceutical group R-Pharm acquired a license to manufacture narlaprevir from the Merck & Co. (MSD).^[12] Further development of the drug was conducted by R-Pharm in cooperation with Texas Liver Institute (USA), with the support of the Federal Target Program "Development of the Pharmaceutical and Medical Industry of the Russian Federation for the period up to 2020 and beyond".^[9] About 700 million rubles were invested in clinical trials and the development of the drug,^[4]^[13] of which 120 million rubles came from the Russian Government.^[14]

Preclinical and clinical studies of the drug were conducted in Schering-Plough Research Institute (USA), as well as in a number of clinical centers in Europe, USA and Russia.^[9]^[13]^[14]The drug is manufactured at a pharmaceutical factory in the Russian city of Yaroslavl.^[4]

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References

1 2 3 "Russian State Registry of Medicines. Arlansa (narlaprevir) film-coated tablets: Registration sertificate" (in Russian). Retrieved 11 January 2017.
1 2 3 4 5 Tong X, Arasappan A, Bennett F, Chase R, Feld B, Guo Z, et al. (June 2010). "Preclinical characterization of the antiviral activity of SCH 900518 (narlaprevir), a novel mechanism-based inhibitor of hepatitis C virus NS3 protease". Antimicrobial Agents and Chemotherapy. 54 (6): 2365–70. doi:10.1128/AAC.00135-10. PMC 2876368 . PMID 20308381.
↑ Chen KX, Njoroge FG (2012). "12. Discovery of Boceprevir and Narlaprevir: The First and Second Generation of HCV NS3 Protease Inhibitors". In Huang X, Aslanian RG (eds.). Case Studies in Modern Drug Discovery and Development. Oxford: John Wiley & Sons, Inc. pp. 296–335. doi:10.1002/9781118219683.ch12. ISBN 9781118219683.
1 2 3 4 "Российский препарат от гепатита С готовится к выпуску" (in Russian). Собеседник.RU. 30 June 2016.
↑ Wang H, Geng L, Chen BZ, Ji M (October 2014). "Computational study on the molecular mechanisms of drug resistance of Narlaprevir due to V36M, R155K, V36M+R155K, T54A, and A156T mutations of HCV NS3/4A protease". Biochemistry and Cell Biology. 92 (5): 357–69. doi:10.1139/bcb-2014-0039. PMID 25178998.
1 2 Rudakova AV, Gusev DA, Uskov AN, Konovalova LN, Lobzin YV (2016). "Cost-Effectiveness of the Second Wave of Protease Inhibitors in the Treatment of Chronic Hepatitis C (Genotype 1) in Patients Not Previously Treated with Antiviral Drugs, and for Relapsed Disease". Journal of Infectology (in Russian). 8 (1): 79–82. doi:10.22625/2072-6732-2016-8-1-79-82 (inactive 31 January 2024).{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
↑ Arasappan A, Bennett F, Bogen SL, Venkatraman S, Blackman M, Chen KX, et al. (May 2010). "Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor". ACS Medicinal Chemistry Letters. 1 (2): 64–9. doi:10.1021/ml9000276. PMC 4007962 . PMID 24900178.
1 2 Bakulin I. "The "Second Wave" PI Narlaprevir in Russian Patients with Genotype 1 Chronic Hepatitis C" (PDF).
1 2 3 4 5 ""R-Pharm" Launches Narlaprevir — a New Oral Medication for Hepatitis C" (in Russian). R-Pharm.com. 6 June 2016. Archived from the original on 28 August 2016. Retrieved 23 December 2016.
↑ Reesink H, Bergmann J, de Bruijne J, Weegink C, Van Lier J, Van Vliet A, et al. (2009). "Safety and Antiviral Activity of SCH 900518 Administered as Monotherapy and in Combination with Peginterferon Alfa-2B to Naive and Treatment-Experienced HCV-1 Infected Patients". Journal of Hepatology. 50 (Supp. 1): S35–S36. doi:10.1016/S0168-8278(09)60088-X.
↑ Bakulin IG, Abdurakhmanov DT, Bogomolov PO, Burnevich EZ, Voloshina NB, Geivandova NI, et al. "Preliminary Results of a Phase III Study of New Protease Inhibitor Narlaprevir in Treatment-Naïve and Treatment-Experienced Patients with Chronic Hepatitis C Genotype 1 (PIONEER Study)" (PDF) (in Russian). p. 20.{{cite web}}: Check |url= value (help)
↑ Dranishnikova M, Fomchenko D (21 June 2012). "Together Against Hepatitis" (in Russian). Vedomosti.
1 2 Lapin M (30 June 2016). "Manufacturing of Hepatitis C Drug Will Begin in Russia" (in Russian). Archived from the original on 24 December 2016. Retrieved 23 December 2016.
1 2 Nevinnaya I. "Minpromtorg Supports the Development of New Drugs" (in Russian). No. Federal Issue No. 5823 (150). Rossiyskaya Gazeta.