Narlaprevir

HCV NS3 protease inhibitor CAS# 865466-24-6

Narlaprevir

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Chemical structure

Narlaprevir

3D structure

Chemical Properties of Narlaprevir

Cas No. 865466-24-6 SDF Download SDF
PubChem ID 11857239 Appearance Powder
Formula C36H61N5O7S M.Wt 707.96
Type of Compound N/A Storage Desiccate at -20°C
Synonyms SCH 900518
Solubility DMSO : ≥ 50 mg/mL (70.63 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical 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
SMILES CCCCC(C(=O)C(=O)NC1CC1)NC(=O)C2C3C(C3(C)C)CN2C(=O)C(C(C)(C)C)NC(=O)NC4(CCCCC4)CS(=O)(=O)C(C)(C)C
Standard InChIKey RICZEKWVNZFTNZ-LFGITCQGSA-N
Standard 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Narlaprevir

DescriptionNarlaprevir is a  potent, selective, orally bioavailable inhibitor of NS3 protease with Ki and EC90 values of 6 nM and 40 nM, respectively.
TargetsNS3 protease    
IC50(Ki=6 nM; EC90=40 nM)     

Narlaprevir Dilution Calculator

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Preparing Stock Solutions of Narlaprevir

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.4125 mL 7.0625 mL 14.1251 mL 28.2502 mL 35.3127 mL
5 mM 0.2825 mL 1.4125 mL 2.825 mL 5.65 mL 7.0625 mL
10 mM 0.1413 mL 0.7063 mL 1.4125 mL 2.825 mL 3.5313 mL
50 mM 0.0283 mL 0.1413 mL 0.2825 mL 0.565 mL 0.7063 mL
100 mM 0.0141 mL 0.0706 mL 0.1413 mL 0.2825 mL 0.3531 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Narlaprevir

Narlaprevir is a potent and second generation inhibitor of HCV NS3 protease with Ki value of 6 nM [1].

HCV infection is a global problem of public health. It can even cause liver cirrhosis and hepatocellular carcinoma. As an essential enzyme of HCV replication, NS3 serine protease is thought to be an attractive target for HCV infection treatment. Narlaprevir is one of the small inhibitors of NS3 protease. Unlike boceprevir, narlaprevir is a single isoform and shows improved potency. In the inhibiting process of NS3 protease, narlaprevir firstly binds the enzyme with noncovalent interactions and then binds the active-site Ser139 with a reversible covalent bond [1, 2 and 3].

In the in vitro assay, narlaprevir inhibited genotyoes 1a, 1b, 2a and 3a NS3 proteases with Ki values of 0.7, 7, 3 and 7 nM, respectively. In the virus replicon-inhibition assay, narlaprevir showed significant antiviral efficacy with EC50 and EC90 values of 20 and 40 nM, respectively. Besides that, narlaprevir had no cytotoxicity for the host cells. Narlaprevir is also used as a combination therapy with pegylated interferon. The combination treatment of narlaprevir and interferon alfa-2b showed elevated activity in replicon inhibition than the monotherapy of narlaprevir alone [2].

Narlaprevir has improved pharmacokinetic profile of both AUC and bioavailability in animal trials. It showed AUC of 6.5 μM·h, 1.1 μM·h and 0.9 μM·h in rats, monkeys and dogs, respectively. The bioavailabilities of narlaprevir in the three kinds of animals are 46%, 46% and 29%, respectively [1].

Some drug resistant mutations have been identified in the selection with high concentrations of narlaprevir, such as A156T (EC50 value of 1 μM), T54A (EC50 value of 11 nM) and the double mutation (T54A and A156T). Narlaprevir was also found to have cross-resistance to the mutations, such as V170A, F43C and V36M (EC50 value of 8 nM), which are resistant against boceprevir [2, 3].

References:
[1].  Arasappan A, Bennett F, Bogen S L, et al. Discovery of narlaprevir (SCH 900518): a potent, second generation HCV NS3 serine protease inhibitor. ACS Medicinal Chemistry Letters, 2010, 1(2): 64-69.
[2].  Tong X, Arasappan A, Bennett F, et al. 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, 2010, 54(6): 2365-2370.
[3].  Wang H, Geng L, Chen B Z, et al. 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, 2014, 92(5): 357-369.

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References on Narlaprevir

Pharmacokinetics of the New Hepatitis C Virus NS3 Protease Inhibitor Narlaprevir following Single-Dose Use with or without Ritonavir in Patients with Liver Cirrhosis.[Pubmed:27645244]

Antimicrob Agents Chemother. 2016 Nov 21;60(12):7098-7104.

In this study we sought to evaluate Narlaprevir (NVR) pharmacokinetics (PK) after a single dose with or without ritonavir (RTV) in cirrhotic versus healthy subjects. NVR at 200 mg was administered to 8 healthy and 8 cirrhotic subjects, and NVR at 100 mg with RTV at 100 mg was administered to 8 healthy and 8 cirrhotic subjects. PK analysis was performed. The geometric mean maximum concentration of a drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUC0-infinity) were 563.1 ng/ml and 4,701.8 ng . h/ml in cirrhotic patients versus 364.8 ng/ml and 1,917.1 ng . h/ml in healthy volunteers, respectively. The geometric mean ratios of the PK parameters of cirrhotic subjects to healthy volunteers were 1.54-fold (90% confidence interval [CI] = 1.05 to 2.27) for Cmax and 2.45-fold (90% CI = 1.56 to 3.85) for AUC0-infinity The geometric mean Cmax and AUC0-infinity in cirrhotic and healthy subjects were similar: 1,225.7 ng/ml for Cmax and 15,213.1 ng . h/ml for AUC0-infinity in cirrhotic subjects and 1,178.9 ng/ml for Cmax and 14,257.2 ng . h/ml for AUC0-infinity in healthy volunteers. The corresponding geometric mean ratios were 1.04 (90% CI = 0.67 to 1.62) for Cmax and 1.07 (90% CI = 0.72 to 1.58) for AUC0-infinity Higher exposures in cirrhotic subjects were safe and well tolerated. We found that NVR exposures after a 200-mg single dose were higher in cirrhotic subjects than in healthy subjects and that a 100-mg single dose of NVR boosted with RTV at 100 mg resulted in no significant PK differences between cirrhotic and healthy subjects.

Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor.[Pubmed:24168257]

J Viral Hepat. 2013 Nov;20(11):779-89.

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with Narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by Narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After Narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after Narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with Narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients.

Sustained virologic response after therapy with the HCV protease inhibitor narlaprevir in combination with peginterferon and ribavirin is durable through long-term follow-up.[Pubmed:23490393]

J Viral Hepat. 2013 Apr;20(4):e78-81.

Achievement of a sustained virologic response (SVR) after peginterferon (PEG-IFN) and ribavirin (RBV) treatment is considered to be a marker for the cure of chronic hepatitis C virus (HCV) infection. Long-term follow-up of patients with SVR after treatment with a direct acting antiviral has not yet been described. We used a randomized placebo-controlled, double-blind, two-period phase 1b trial that was conducted in 40 HCV genotype 1 (treatment-naive and treatment-experienced)-infected patients. Nineteen patients achieved SVR after treatment with the HCV protease inhibitor Narlaprevir followed by PEG-IFN/RBV. In these patients, HCV-RNA tests were scheduled at 3, 6, 12 and 24 months after end of treatment. Patients were followed for a median of 27 months (range 15-32) after end of treatment with a median number of follow-up visits of 4 (range 3-8). All patients remained HCV-RNA negative over time. SVR achieved following Narlaprevir and PEG-IFN/RBV-therapy was durable up to 32 months after the end of treatment.

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.[Pubmed:25178998]

Biochem Cell Biol. 2014 Oct;92(5):357-69.

Narlaprevir is a novel NS3/4A protease inhibitor of hepatitis C virus (HCV), and it has been tested in a phase II clinical trial recently. However, distinct drug-resistance of Narlaprevir has been discovered. In our study, the molecular mechanisms of drug-resistance of Narlaprevir due to the mutations V36M, R155K, V36M+R155K, T54A, and A156T of NS3/4A protease have been investigated by molecular dynamics (MD) simulations, free energy calculations, and free energy decomposition analysis. The predicted binding free energies of Narlaprevir towards the wild-type and five mutants show that the mutations V36M, R155K, and T54A lead to low-level drug resistance and the mutations V36M+R155K and A156T lead to high-level drug resistance, which is consistent with the experimental data. The analysis of the individual energy terms indicates that the van der Waals contribution is important for distinguishing the binding affinities of these six complexes. These findings again show that the combination of different molecular modeling techniques is an efficient way to interpret the molecular mechanism of drug-resistance. Our work mainly elaborates the molecular mechanism of drug-resistance of Narlaprevir and further provides valuable information for developing novel, safer, and more potent HCV antiviral drugs in the near future.

Description

Narlaprevir is a potent, selective, orally bioavailable NS3 protease inhibitor(Ki=6 nM; EC90=40 nM)

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