Home Proteases HCV Protease inhibitor - COVID-19 inhibitor Danoprevir

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Danoprevir HCV Protease inhibitor

Cat.No.S1183

Danoprevir is a peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV) with IC50 of 0.2-3.5 nM, inhibition effect for HCV genotypes 1A/1B/4/5/6 is ~10-fold higher than 2B/3A. Phase 2.
Danoprevir HCV Protease inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 731.83

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Quality Control

Batch: S118301 DMSO]144 mg/mL]false]Ethanol]144 mg/mL]false]Water]Insoluble]false Purity: 99.94%
99.94

Chemical Information, Storage & Stability

Molecular Weight 731.83 Formula

C35H46FN5O9S

 Storage (From the date of receipt)
CAS No. 850876-88-9 Download SDF Storage of Stock Solutions

Synonyms ITMN-191, RG7227 Smiles CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(NC(=O)C3CC(CN3C1=O)OC(=O)N4CC5=C(C4)C(=CC=C5)F)C(=O)NS(=O)(=O)C6CC6

Solubility

In vitro
Batch:

DMSO : 144 mg/mL (196.76 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 144 mg/mL

Water : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Features
A peptidomimetic inhibitor of the NS3/4A protease of hepatitis C virus (HCV).
Targets/IC50/Ki
HCV NS3/4A protease [1]
0.2 nM-3.5 nM
In vitro

Danoprevir (0.29 nM) inhibits the reference genotype 1 NS3/4A protease half-maximally, but a high dose of this compound (10 μM) shows no appreciably inhibition in a panel of 79 proteases, ion channels, transporters, and cell surface receptors. It remains bound to and inhibits NS3/4A for more than 5 hours after its initial association. This chemical (45 nM) eliminates a patient-derived HCV genotype 1b replicon from hepatocyte-derived Huh7 cells with an EC50 of 1.8 nM. [1] In HCV subgenomic replicon cell lines containing the individual mutations, V36M, R109K, and V170A substitutions confer little or no resistance to it, but the R155K substitution confers a high level (62-fold increase) of resistance to this compound. [2] In Huh7.5 cells transfected with chimeric recombinant virus, it shows antiviral inhibition effects against HCV genotypes 1, 4 and 6 with IC50 of 2-3 nM, which are >100-fold lower than genotypes 2/3/5 (280-750 nM). [3]
Kinase Assay
Continuous fluorescent resonance energy transfer (FRET) assay
The assay buffer contains 25 μM NS4A peptide, 50 mM Tris-HCl, pH 7.5, 15% vol/vol, 10 mM dithiothreitol, and 0.5 μM QXL520-labeled FRET substrate {Ac-DE-Dap(QXL520)-EE-Abu-ψ-[COO]-AS-Cys(5-FAMsp)-NH2}. K2040 enzyme (50 pM) is added to initiate the reaction. Reactions are set up in black 96-well plates, and fluorescence data is collected. Control reactions lacking inhibitors and enzyme are included. Initial rates are calculated from the linear phase of the reaction (up to 1 hour) and are used to obtain IC50. Recovery of activity from preformed this compound-NS3/4A complex is assessed by preincubating 10 nM NS3/4A with a two-fold excess of this chemical in 1× assay buffer for 15 min, followed by a rapid 200-fold dilution of the preformed complex into assay buffer containing substrate. A control reaction with the same final conditions without preincubation of NS3/4A and this compound is initiated by the addition of enzyme to an otherwise-complete reaction mixture. Additional control reactions lack either this chemical or NS3. The progress of the reactions is followed over 5 hours.
In vivo

Danoprevir (30 mg/kg) administered to rats or monkeys shows that its concentrations in liver 12 hours after dosing exceed the concentration of this compound required to eliminate replicon RNA from cells. [1]
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01714154 Completed
Healthy Volunteer
Hoffmann-La Roche
 November 2012 Phase 1
NCT01592318 Completed
Healthy Volunteer
Hoffmann-La Roche
 May 2012 Phase 1
NCT01588002 Completed
Healthy Volunteer
Hoffmann-La Roche
 April 2012 Phase 1
NCT01519336 Completed
Healthy Volunteer
Hoffmann-La Roche
 February 2012 Phase 1

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