Lomibuvir (VX-222)

ArtNr	S1480-5000
Hersteller	Selleckchem
CAS-Nr.	1026785-59-0
Menge	5 g
Quantity options	10 mg 1 g 10 g 10 mM/1 ml 200 mg 5 mg 50 mg 5 g
Kategorie	Inhibitors & Compound Libraries Small Molecules
Typ	Inhibitors
Specific against	other
Smiles	CC1CCC(CC1)C(=O)N(C2CCC(CC2)O)C3=C(SC(=C3)C#CC(C)(C)C)C(=O)O
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	VCH-222
Similar products	VX-222, 1026785-55-6
Lieferbar
Storage Conditions	2 years -80 in solvent
Molecular Weight	445, 61
Administration	By oral gavage
Animal Models	Rats or dogs
Cell lines	Huh7.5 cells
Clinical Trials	VX-222, associated with Telaprevir, Peginterferon-Alfa-2a, and Ribavirin, is currently under Phase II clinical trials covering chronic hepatitis C virus-infected patients.
Concentrations	0.01 nM -10 uM
Dosages	5 mg/kg for rats or 10 mg/kg for dogs
Formulation	Dissolved in 30% PEG
IC50	0.94 uM, 0.94 uM, 0.94 uM, 0.94 uM, 0.94 uM, 0.94 uM
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 uM, 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 pro le, 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]
Incubation Time	48 hours
Kinase Assay	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 uM) is tested in the presence of 10 to 75 uM nonradioactive UTP mixed with 0.89 to 6.70 uCi of [alpha-33P]-labeled UTP. RNA-dependent-RNA polymerase reactions are allowed to proceed for 18 min at 22 C.
Method	Huh7.5 cells harboring HCV RNA replicons are trypsinized and plated into 48-well plates at a concentration of 4 x 104 cells/well. The next day the medium is changed and VX-222 is added in 200 uL of complete medium. After 48 hours, total RNA is extracted and viral RNAs are quanti ed 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 tting.
Solubility (25C)	DMSO 89 mg/mL, Water <1 mg/mL, Ethanol 89 mg/mL
Information	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.
Chemical Name	5-(3, 3-dimethylbut-1-ynyl)-3-((1r, 4R)-N-((1r, 4R)-4-hydroxycyclohexyl)-4-methylcyclohexanecarboxamido)thiophene-2-carboxylic acid
Features	VX-222 is a novel, potent and selective inhibitor of non-nucleoside polymerase, specifically the HCV RNA-dependent RNA polymerase.

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