Lomibuvir (VX-222)

For research use only.

Catalog No.S1480 Synonyms: VCH-222

15 publications

Lomibuvir (VX-222) Chemical Structure

CAS No. 1026785-59-0

Lomibuvir (VX-222, VCH-222) is a novel, potent and selective inhibitor of HCV polymerase with IC50 of 0.94-1.2 μM, 15.3-fold less effective for mutant M423T, and 108-fold less effective for mutant I482L. Phase 2.

Selleck's Lomibuvir (VX-222) has been cited by 15 publications

1 Customer Review

  • Genetic barriers of JTK-853, NNI-A, PF-868554, VX-222, PSI-6130, BMS-790052, and TMC435 for Con1. VX-222 and the other DAAs were treated at 1/3xEC90 for 17 days.

    Intervirology 2013 56(5), 302-9. Lomibuvir (VX-222) purchased from Selleck.

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Biological Activity

Description Lomibuvir (VX-222, VCH-222) is a novel, potent and selective inhibitor of HCV polymerase with IC50 of 0.94-1.2 μM, 15.3-fold less effective for mutant M423T, and 108-fold less effective for mutant I482L. Phase 2.
Features A novel, potent and selective inhibitor of non-nucleoside polymerase, specifically the HCV RNA-dependent RNA polymerase.
Targets
HCV NS5B 1a [1] HCV NS5B 1b [1]
0.94 μM 1.2 μM
In vitro

VX-222 binds to the thumb II allosteric pocket of the HCV RNA-dependent RNA polymerase. VX-222 exhibits non-competitive and selective inhibition in HCV NS5B of genotype 1a and 1b, with IC50 of 0.94 and 1.2 μM, respectively. VX-222 selectively inhibits the replication of subgenomic HCV genotype 1a and 1b with an EC50 of 22.3 and 11.2 nM, respectively. [1] Similarly, a recent study shows that VX-222 inhibits the 1b/Con1 HCV subgenomic replicon, with an EC50 of 5 nM. VX-222 preferentially inhibits primer-dependent RNA synthesis, showing only a modest or no effect on de novo-initiated RNA synthesis. [2]

In vivo In rats and dogs, VCH-222 displays fine pharmacokinetic profile, including low total body clearance and excellent oral bioavailability (greater than 30%) and good ADME properties. VCH-222 is biotransformed by several enzymes (CYP1A1, 2A6, 2B6, 2C8, CYP 3A4, UGT1A3) and is predicted to be actively transported in liver and excreted mainly intact in bile or as glucuronide adducts. [3]

Protocol

Kinase Assay:[1]
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Anti-NS5B activity assay:

The inhibitory effect of VX-222 on HCV NS5B activity is measured by evaluating the amount of radiolabeled UTP incorporated by the C-terminal ∆21 truncated version of enzyme in a newly synthesized RNA using a homopolymeric RNA template / primer namely poly rA / oligo dT. Quantitative detection of incorporated radioactivity is done using a liquid scintillation counter. The in vitro kinetics of inhibition of HCV NS5B from genotype 1b strain BK by VX-222 are determined using the C-terminal ∆21 truncated version of NS5B. VX-222 (1 to 1.5 μM) is tested in the presence of 10 to 75 μM nonradioactive UTP mixed with 0.89 to 6.70 μCi of [α-33P]-labeled UTP. RNA-dependent-RNA polymerase reactions are allowed to proceed for 18 min at 22 °C.
Cell Research:[2]
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  • Cell lines: Huh7.5 cells
  • Concentrations: 0.01 nM -10 μM
  • Incubation Time: 48 hours
  • Method: Huh7.5 cells harboring HCV RNA replicons are trypsinized and plated into 48-well plates at a concentration of 4 × 104 cells/well. The next day the medium is changed and VX-222 is added in 200 μL of complete medium. After 48 hours, total RNA is extracted and viral RNAs are quantified by real-time reverse transcription-PCR (RT-PCR). The effective drug concentrations that reduced HCV RNA replicon levels by 50% (EC50) are calculated by nonlinear regression analysis with log curve fitting.
    (Only for Reference)
Animal Research:[3]
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  • Animal Models: Rats or dogs
  • Dosages: 5 mg/kg for rats or 10 mg/kg for dogs
  • Administration: By oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 89 mg/mL (199.72 mM)
Ethanol 89 mg/mL (199.72 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% PEG400+0.5% Tween80+5% propylene glycol
For best results, use promptly after mixing. 		30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 445.61
Formula

C25H35NO4S
CAS No. 1026785-59-0
Storage powder
in solvent
Synonyms VCH-222
Smiles CC1CCC(CC1)C(=O)N(C2CCC(CC2)O)C3=C(SC(=C3)C#CC(C)(C)C)C(=O)O

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00958152 Completed Drug: VCH-222|Drug: telaprevir Hepatitis C Vertex Pharmaceuticals Incorporated August 2009 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID