5-(3,3-dimethylbut-1-yn-1-yl)-3-{N-[(1s,4s)-4-hydroxycyclohexyl](1r,4r)-4-methylcyclohexaneamido}thiophene-2-carboxylic acid

• ChemBase ID: 72702
• Molecular Formular: C25H35NO4S
• Molecular Mass: 445.6147
• Monoisotopic Mass: 445.22867961
• SMILES: [C@H]1(CC[C@@H](CC1)O)N(c1c(sc(c1)C#CC(C)(C)C)C(=O)O)C(=O)[C@@H]1CC[C@H](CC1)C
• Canonical SMILES: O[C@@H]1CC[C@@H](CC1)N(c1cc(sc1C(=O)O)C#CC(C)(C)C)C(=O)[C@@H]1CC[C@H](CC1)C
• InChI: InChI=1S/C25H35NO4S/c1-16-5-7-17(8-6-16)23(28)26(18-9-11-19(27)12-10-18)21-15-20(13-14-25(2,3)4)31-22(21)24(29)30/h15-19,27H,5-12H2,1-4H3,(H,29,30)/t16-,17-,18-,19+
• InChIKey: WPMJNLCLKAKMLA-UGLKCIBTSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 5-(3,3-dimethylbut-1-yn-1-yl)-3-{N-[(1s,4s)-4-hydroxycyclohexyl](1r,4r)-4-methylcyclohexaneamido}thiophene-2-carboxylic acid
• IUPAC Traditional name: 5-(3,3-dimethylbut-1-yn-1-yl)-3-{N-[(1s,4s)-4-hydroxycyclohexyl](1r,4r)-4-methylcyclohexaneamido}thiophene-2-carboxylic acid
• Synonyms: VX222; VCH222; VX-222

Database IDs

• CAS Number: 1026785-59-0
• PubChem SID: 162037623
• PubChem CID: 24798764

CALCULATED PROPERTIES

• Acid pKa: 3.5708838
• H Acceptors: 4
• H Donor: 2
• LogD (pH = 5.5): 3.68646
• LogD (pH = 7.4): 2.2569177
• Log P: 5.6098995
• Molar Refractivity: 120.6994 cm^3
• Polarizability: 47.437763 Å^3
• Polar Surface Area: 77.84 Å^2
• Rotatable Bonds: 6
• Lipinski's Rule of Five: false

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: HCV protease

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1480

Research Area

• Description: Cancer

Biological Activity

• Description: VX-222 (VCH-222) is a novel, potent and selective inhibitor of HCV polymerase with IC50 of 0.94-1.2 μM.
• Targets: HCV NS5B 1a; HCV NS5B 1b
• IC50: 0.94 μM; 1.2 μM ^[1]
• 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 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]
• 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.
• Features: VX-222 is a novel, potent and selective inhibitor of non-nucleoside polymerase, specifically the HCV RNA-dependent RNA polymerase.

Protocol

• Protocol: Kinase Assay ^[1]
• 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.
• Protocol: Cell Assay ^[2]
• Cell Lines: Huh7.5 cells
• Concentrations: 0.01 nM -10 μM
• Incubation Time: 48 hours
• Methods: Huh7.5 cells harboring HCV RNA replicons are trypsinized and plated into 48-well plates at a concentration of 4 × 10^4 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 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.
• Protocol: Animal Study ^[3]
• Animal Models: Rats or dogs
• Formulation: Dissolved in 30% PEG
• Doses: 5 mg/kg for rats or 10 mg/kg for dogs
• Administration: By oral gavage

References

• References: [1] Bedard J, et al. J Hepatol, 2009, 50(Suppl 1), S340.
• References: [2] Yi G, et al. Antimicrob Agents Chemother, 2012, 56(2), 830-837.
• References: [3] Chauret N, et al. J Hepatol, 2009, 50(Suppl 1), S341-S342.

REFERENCES

• Bedard J, et al. J Hepatol, 2009, 50(Suppl 1), S340.
• Yi G, et al. Antimicrob Agents Chemother, 2012, 56(2), 830-837.
• Chauret N, et al. J Hepatol, 2009, 50(Suppl 1), S341-S342.