1. Anti-infection
    Metabolic Enzyme/Protease
  2. HCV
    HCV Protease

Simeprevir (Synonyms: TMC435)

Cat. No.: HY-10241 Purity: 99.98%
Data Sheet SDS Handling Instructions

Simeprevir is a potent HCV NS3/4A protease inhibitor, and inhibits HCV replication with EC50 of 8 nM.

For research use only. We do not sell to patients.
Simeprevir Chemical Structure

Simeprevir Chemical Structure

CAS No. : 923604-59-5

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    Simeprevir purchased from MCE. Usage Cited in: Int J Radiat Oncol Biol Phys. 2016 Nov 15;96(4):867-876.

    Simeprevir inhibits DNA damage repair following irradiation. U251, BT474, and HepG2 cells are pretreated with Simeprevir or DMSO and irradiated at a dose of 6 Gy. After 6 hours, prolongation of γH2AX foci is detected in Simeprevir-treated cells along with decreased phosphorylation of DNA-PKcs, indicating impaired nonhomologous end-joining repair.

    Simeprevir purchased from MCE. Usage Cited in: J Med Chem. 2016 Nov 23;59(22):10268-10284.

    Huh7.5 cells are infected with HCV (45 IU/cell) and simultaneously treated with Simeprevir (A, 0.025 μM), Sofosbuvir (B, 0.1 μM), or Daclatasvir (C, 16 pM) alone or with 1 (6.25 μM).

    Simeprevir purchased from MCE. Usage Cited in: Biomed Res Int. 19 July 2017.

    Huh7.5 (HCV+) cells are treated with 1 μM of Simeprevir or solvent control. At 24 hours, the cells are washed and continuously incubated with fresh culture media containing drugs again for 48 hours. The cultural supernatants are then harvested and directly incubated to naïve Huh7.5 cells. After been passaged 1~3 times, the newly infected cells are treated with 1 μM of Simeprevir for 72 hours. Intracellular proteins are extracted and detected with WB.

    Simeprevir purchased from MCE. Usage Cited in: Biomed Res Int. 19 July 2017.

    Huh7.5 (HCV+) cells are treated with 1 μM of Sofosbuvir or solvent control. At 24 hours, the cells are washed and continuously incubated with fresh culture media containing drugs again for 48 hours. The cultural supernatants are then harvested and directly incubated to naïve Huh7.5 cells. After been passaged 1~3 times, the newly infected cells are treated with 1 μM of Sofosbuvir for 72 hours. Intracellular proteins are extracted and detected with WB.

    Simeprevir purchased from MCE. Usage Cited in: Biomed Res Int. 19 July 2017.

    Naïve Huh7.5 cells are infected with wild and mutant type HCV and simultaneously treated with drugs. Intracellular proteins were extracted and detected with WB in 72 hours. Telaprevir (VX-950) against WT and A156T mutant HCV.
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    Simeprevir is a potent HCV NS3/4A protease inhibitor, and inhibits HCV replication with EC50 of 8 nM.

    IC50 & Target

    EC50: 8 nM

    In Vitro

    In Huh7-Luc cells, antiviral activity of simeprevir (TMC435350) is dose dependent, and the EC50 and EC90 values determined for TMC435350 are 8 nM and 24 nM, respectively. Inhibition of TMC435350 on NS3/4A protease is time dependent, and the overall Kis are estimated to be 0.5 nM for genotype 1a and 0.4 nM for genotype 1b, respectively[1]. TMC435350 is a potent inhibitor of HCV NS3/4A protease (Ki=0.36 nM) and viral replication (replicon EC50=7.8 nM)[2].

    In Vivo

    In rats, TMC435350 (40 mg/kg, p.o.) is extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability is 44%[1].

    Clinical Trial
    NCT Number Sponsor Condition Start Date Phase
    NCT02250807 Janssen R&D Ireland Chronic Hepatitis C|Genotype 4 Chronic Hepatitis C January 2015 Phase 3
    NCT02512562 Alios Biopharma Inc.|Achillion Pharmaceuticals Chronic Hepatitis C July 2015 Phase 1
    NCT02206932 University of California, San Francisco|Janssen Scientific Affairs, LLC Hepatitis C, Chronic|HIV CDC Category A1 Phase 4
    NCT02268864 Janssen-Cilag International NV Hepatitis C, Chronic January 2015 Phase 2
    NCT01707342 Janssen R&D Ireland Healthy Male Participants October 2012 Phase 1
    NCT02253550 Peter J. Ruane, M.D.|Janssen Scientific Affairs, LLC|Peter J. Ruane, M.D., Inc. Chronic Hepatitis C October 2014 Phase 2
    NCT02624063 Federal University of São Paulo Hepatitis C, Chronic December 2015 Phase 4
    NCT02702739 Azienda Ospedaliera San Camillo Forlanini Liver Cirrhosis January 2015 Phase 4
    NCT02114151 Janssen Infectious Diseases BVBA Hepatitis C Virus Infection April 2014 Phase 3
    NCT02262728 Janssen Research & Development, LLC Hepatitis C, Chronic September 2014 Phase 2
    NCT02114177 Janssen Infectious Diseases BVBA Hepatitis C Virus Infection April 2014 Phase 3
    NCT02404805 University of Colorado, Denver HIV|Hepatitis C February 2016
    NCT02278419 Janssen-Cilag International NV Hepatitis C December 2014 Phase 2
    NCT02397395 Janssen R&D Ireland Renal Impairment|End-stage Renal Disease May 2015 Phase 2
    NCT03069001 Ain Shams University HCV June 2015 Phase 4
    NCT01907724 Merck Sharp & Dohme Corp.|Janssen Research & Development, LLC Hepatitis C, Chronic May 2013 Phase 1
    NCT01813513 Merck Sharp & Dohme Corp. Chronic Hepatitis C Infection January 2013 Phase 1
    NCT02485080 Stanford University|Janssen Scientific Affairs, LLC|Yale University PT-NANBH September 2015 Phase 4
    NCT02165189 Janssen Scientific Affairs, LLC Hepatitits C August 2014 Phase 2
    NCT02421211 Janssen Sciences Ireland UC Hepatitis C, Chronic May 19, 2015 Phase 2
    NCT02349048 Janssen Research & Development, LLC Hepatitis C Virus January 2015 Phase 2
    NCT02765490 Janssen Research & Development, LLC Hepatitis C, Chronic November 9, 2016 Phase 2
    NCT02945020 Janssen Research & Development, LLC Healthy November 10, 2016 Phase 1
    NCT01628692 Bristol-Myers Squibb|Janssen Research & Development, LLC Hepatitis C Virus July 2012 Phase 2
    NCT02824315 Janssen Research & Development, LLC Healthy May 2016 Phase 1
    NCT02993250 Janssen Pharmaceutical K.K. Hepatitis C, Chronic December 21, 2016 Phase 2
    NCT02569710 Alios Biopharma Inc. Chronic Hepatitis C October 31, 2015 Phase 2
    NCT01938625 Janssen R&D Ireland Hepatitis C, Chronic December 2013 Phase 2
    NCT02885454 Janssen Research & Development, LLC Healthy August 2016 Phase 1
    NCT03059303 Janssen Research & Development, LLC Healthy February 20, 2017 Phase 1
    NCT02168361 Center For Hepatitis C, Atlanta, GA Chronic Hepatitis C December 2013 Phase 4
    NCT01852604 Merck Sharp & Dohme Corp.|Janssen Research & Development, LLC Chronic Hepatitis C Virus March 2013 Phase 2
    NCT02485262 Arrowhead Regional Medical Center Hepatitis C November 2013
    NCT02118597 Hoffmann-La Roche Hepatitis C, Chronic May 2014
    NCT02214420 SC Liver Research Consortium, LLC|Janssen, LP Hepatitis C October 2014 Phase 4
    NCT02771405 National Hepatology & Tropical Medicine Research Institute|Cairo University Hepatitis C, Chronic|Hepatocellular Carcinoma March 2016 Phase 3
    NCT02992457 Tanta University Hepatitis C December 2016 Phase 4
    NCT02758509 Parc de Salut Mar Chronic Hepatitis C|Cirrhosis January 1, 2010
    NCT02333292 Valme University Hospital|Hospital del SAS de Jerez|Hospital General Universitario Elche|Hospital La Línea de la Concepción|Complexo Hospitalario Universitario de A Coruña|Hospital de Figueres|Hospital Universitario Puerto Real|Hospital Universitario Virgen de la Victoria|Hospital Universitario de Canarias|Hospital General Universitario de Alicante|Hospital Universitario Araba|Hospital Royo Vilanova|Hospital Universitario de Burgos|Complejo Hospitalario Universitario de Huelva|Hospital Universitario Reina Sofia|Hospital Universitario Virgen Macarena|Complexo Hospitalario Universitario de Vigo|Clinica Universidad de Navarra, Universidad de Navarra|Hospital Clinico Universitario San Cecilio|Hospital Universitario La Fe|Hospital General Universitario de Valencia|Hospital Universitario Infanta Leonor|Hospital Universitario de Gran Canaria|Hospital General Universitario Santa Lucía|Centro Penitenciario Alicante 1|Hospital Regional Universitario Carlos Haya|Hospital Virgen de la Luz|Hospital General Universitario de Castellón|Hospital Parc Taulí, Sabadell Chronic Hepatitis C Infection December 2014
    NCT01891851 Tibotec Pharmaceuticals, Ireland Healthy October 2007 Phase 1
    NCT00752648 Tibotec Pharmaceuticals, Ireland Hepatitis C|HCV July 2008 Phase 1
    NCT00752544 Tibotec Pharmaceuticals, Ireland HCV August 2008 Phase 1
    NCT00938899 Tibotec Pharmaceuticals, Ireland Hepatitis C January 2007 Phase 1
    NCT00741169 Tibotec Pharmaceuticals, Ireland Hepatitis C|HCV|Tuberculosis|Rifampin|Pharmacokinetics June 2008 Phase 1
    NCT01046058 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus January 2010 Phase 1
    NCT01799603 Janssen Research & Development, LLC Healthy May 2012 Phase 1
    NCT01567735 Janssen R&D Ireland Hepatitis C March 27, 2012 Phase 3
    NCT01381835 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus July 2011 Phase 1
    NCT01323244 Janssen R&D Ireland Hepatitis C December 2011 Phase 3
    NCT00915564 Tibotec Pharmaceuticals, Ireland Hepatitis C September 2009 Phase 1
    NCT01224197 Tibotec Pharmaceuticals, Ireland Hepatitis C October 2010 Phase 1
    NCT01090700 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus May 2010 Phase 1
    NCT01022125 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus January 2010 Phase 1
    NCT02071355 Janssen Research & Development, LLC Healthy April 2014 Phase 1
    NCT01689623 Janssen Research & Development, LLC Healthy Participants June 2012 Phase 1
    NCT00866853 Tibotec Pharmaceuticals, Ireland Hepatitis C|Viruses March 2009 Phase 1
    NCT01479881 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus October 2011 Phase 1
    NCT01134718 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus June 2010 Phase 1
    NCT01486004 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus November 2011 Phase 1
    NCT01479868 Janssen R&D Ireland Hepatitis C Virus Genotype-1 October 2011 Phase 3
    NCT01571570 Janssen R&D Ireland Healthy Volunteers March 2012 Phase 1
    NCT01288742 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus January 2011 Phase 1
    NCT01124799 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus July 2010 Phase 1
    NCT01290731 Janssen Pharmaceutical K.K. Hepatitis C, Chronic January 2011 Phase 3
    NCT01846832 Janssen-Cilag International NV Hepatitis C, Chronic|Infection September 2013 Phase 3
    NCT00882908 Tibotec Pharmaceuticals, Ireland Hepatitis C June 2009 Phase 2
    NCT01308606 Tibotec Pharmaceuticals, Ireland Hepatitis C March 2011 Phase 1
    NCT01366638 Janssen Pharmaceutical K.K. Hepatitis C, Chronic May 2011 Phase 3
    NCT01725529 Janssen R&D Ireland Hepatitis C, Chronic November 2012 Phase 3
    NCT01288209 Janssen Pharmaceutical K.K. Hepatitis C, Chronic February 2011 Phase 3
    NCT01241773 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus October 2010 Phase 1
    NCT01289782 Janssen R&D Ireland Hepatitis C February 2011 Phase 3
    NCT01205139 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus November 2010 Phase 1
    NCT01292239 Janssen Pharmaceutical K.K. Hepatitis C, Chronic February 2011 Phase 3
    NCT01323257 Tibotec Pharmaceuticals, Ireland Hepatitis C Virus March 2011 Phase 1
    NCT01281839 Janssen R&D Ireland Hepatitis C February 2011 Phase 3
    NCT01290679 Janssen R&D Ireland Hepatitis C March 2011 Phase 3
    NCT01269294 Tibotec Pharmaceuticals, Ireland Hepatitis C January 2011 Phase 1
    NCT01466790 Janssen R&D Ireland|Gilead Sciences Hepatitis C January 2012 Phase 2
    NCT00980330 Tibotec Pharmaceuticals, Ireland Hepatitis C October 2009 Phase 2
    NCT01485991 Janssen R&D Ireland Hepatitis C February 2012 Phase 3
    NCT02064842 Janssen R&D Ireland Healthy February 2014 Phase 1
    NCT00812331 Tibotec Pharmaceuticals, Ireland Hepatitis C March 2009 Phase 2
    NCT02018536 Janssen R&D Ireland Healthy October 2013 Phase 1
    NCT00996476 Janssen Pharmaceutical K.K. Hepatitis C, Chronic July 2009 Phase 2
    NCT01724086 Janssen R&D Ireland Chronic Hepatitis C October 2012 Phase 2
    NCT00561353 Tibotec Pharmaceuticals, Ireland Hepatitis C, Chronic January 2008 Phase 2
    NCT01202825 Tibotec Pharmaceuticals, Ireland Hepatitis C April 2010 Phase 1
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    References
    Preparing Stock Solutions
    Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
    1 mM 1.3334 mL 6.6672 mL 13.3344 mL
    5 mM 0.2667 mL 1.3334 mL 2.6669 mL
    10 mM 0.1333 mL 0.6667 mL 1.3334 mL
    Kinase Assay
    [1]

    In vitro inhibition of NS3/4A activity is determined using a fluorescence resonance energy transfer cleavage assay with the RetS1 peptide substrate, derived from the genotype 1a NS4A-4B junction, and bacterially expressed full-length NS3 protease domain, supplemented with an NS4A peptide. Briefly, NS3/4A is preincubated in the presence of TMC435350 for 10 min, and then the RetS1 substrate is added and fluorescence is continuously measured for 20 min (excitation, 355 nm; emission, 500 nm). Cleavage of the substrate is expressed as a percentage of the cleavage seen with the vehicle control. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [1]

    Simeprevir is diluted in in a final DMSO concentration of 0.5% in the absence of G418.

    Huh7-Luc cells are seeded at a density of 2,500 cells/well in a 384-well plate in Dulbecco's modified Eagle's medium plus 10% fetal calf serum and incubated with a range of concentrations of serially diluted simeprevir (TMC435350), in a final DMSO concentration of 0.5% in the absence of G418. After 72 h of incubation, Steady Lite reagent is added in a 1:1 ratio to the medium, and luciferase signal is measured using a ViewLux reader.  MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    Twenty-four male specific-pathogen-free Sprague-Dawley rats, weighing between 200 and 300 g at the time of dosing, are divided into eight groups of three rats each. Seven groups are dosed orally (p.o.) by gastric intubation of a vitamin E acetate-d-α-tocopheryl polyethylene glycol 1000 succinate-polyethylene glycol 400 solution of Simeprevir (TMC435350) at 2 mL/kg body weight to provide a dose of 40 mg/kg. One group is dosed intravenously (i.v.) by slow bolus injection in a tail vein of a 20% 2-hydroxypropyl-β-cyclodextrin formulation of TMC435350 (containing TMC435350, 100 mg/mL 2-hydroxypropyl-β-cyclodextrin, 0.1 N NaOH to pH 8.0±0.1, and mannitol-and pyrogen-free water) at 2 mL/kg body weight to provide a dose of 4 mg/kg. Water and food are available ad libitum during the study. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    749.94

    Formula

    C₃₈H₄₇N₅O₇S₂

    CAS No.

    923604-59-5

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    10 mM in DMSO

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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