| Name | Simeprevir |
| Description | Simeprevir (TMC435) is a potent HCV NS3/4A protease inhibitor, and inhibits HCV replication with EC50 of 8 nM. |
| Cell Research | 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, 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. |
| Kinase Assay | 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. |
| Animal Research | 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. |
| In vitro | In Huh7-Luc cells, antiviral activity of simeprevir (Simeprevir) is dose dependent, and the EC50 and EC90 values determined for Simeprevir are 8 nM and 24 nM, respectively. Inhibition of Simeprevir 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. Simeprevir is a potent inhibitor of HCV NS3/4A protease (Ki=0.36 nM) and viral replication (replicon EC50=7.8 nM). |
| 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%. |
| Storage | Shipping with blue ice/Shipping at ambient temperature. |
| Solubility Information | 10% DMSO+40% PEG300+5% Tween 80+45% Saline : 1 mg/mL (1.33 mM), Sonication is recommended.
DMSO : 55 mg/mL (73.34 mM), Sonication is recommended.
H2O : Insoluble
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| Keywords | Virus replication | TMC435350 | TMC-435 | TMC 435350 | TMC 435 | Simeprevir | SARS-CoV | SARSCoV | SARS coronavirus | RNA-dependent RNA polymerase | Remdesivir | RdRp | Inhibitor | inhibit | immune responses | Huh7-Luc | Hepatitis C virus | HCVProtease | HCV Protease | HCV NS3/4A protease | HCV | DNA/RNA Synthesis |
| Inhibitors Related | 5-Fluorouracil | Adenine hemisulfate | Erythromycin thiocyanate | Sofosbuvir | Guanidine hydrochloride | Hydroxychloroquine | Hexane-1,6-diol | 1,4-Naphthoquinone | Adenine | Carbazole | Thymidine | Usnic Acid |
| Related Compound Libraries | Bioactive Compound Library | Approved Drug Library | EMA Approved Drug Library | Drug Repurposing Compound Library | Anti-Viral Compound Library | Inhibitor Library | NO PAINS Compound Library | FDA-Approved Drug Library | Immunology/Inflammation Compound Library | Bioactive Compounds Library Max | Anti-Infection Compound Library | Human Metabolite Library |
United States
