Home Proteases HCV Protease inhibitor Lomibuvir (VX-222)

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Lomibuvir (VX-222) HCV Protease inhibitor

Cat.No.S1480

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

Chemical Structure

Molecular Weight: 445.61

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Quality Control

Batch: S148001 DMSO]89 mg/mL]false]Ethanol]89 mg/mL]false]Water]Insoluble]false Purity: 99.66%
99.66

Chemical Information, Storage & Stability

Molecular Weight 445.61 Formula

C25H35NO4S

 Storage (From the date of receipt)
CAS No. 1026785-59-0 Download SDF Storage of Stock Solutions

Synonyms VCH-222 Smiles CC1CCC(CC1)C(=O)N(C2CCC(CC2)O)C3=C(SC(=C3)C#CC(C)(C)C)C(=O)O

Solubility

In vitro
Batch:

DMSO : 89 mg/mL (199.72 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 89 mg/mL

Water : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Features
A novel, potent and selective inhibitor of non-nucleoside polymerase, specifically the HCV RNA-dependent RNA polymerase.
Targets/IC50/Ki
HCV NS5B 1a [1]
0.94 μM
HCV NS5B 1b [1]
1.2 μM
In vitro
Lomibuvir (VX-222) binds to the thumb II allosteric pocket of the HCV RNA-dependent RNA polymerase. It exhibits non-competitive and selective inhibition in HCV NS5B of genotype 1a and 1b, with IC50 of 0.94 and 1.2 μM, respectively. This compound 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 it 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]
Kinase Assay
Anti-NS5B activity assay
The inhibitory effect of Lomibuvir (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 this compound are determined using the C-terminal ∆21 truncated version of NS5B. It (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.
In vivo
Lomibuvir (VX-222) displays a fine pharmacokinetic profile in rats and dogs, including low total body clearance and excellent oral bioavailability (greater than 30%) with good ADME properties. It is biotransformed by several enzymes (CYP1A1, 2A6, 2B6, 2C8, CYP 3A4, UGT1A3) and is predicted to be actively transported in the liver and excreted mainly intact in bile or as glucuronide adducts. [3]
References

Clinical Trial Information

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

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00958152 Completed
Hepatitis C
Vertex Pharmaceuticals Incorporated
 August 2009 Phase 1

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