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Purity: ≥98%
Simeprevir (previously known as TMC43) is a competitive, reversible, macrocyclic, noncovalent protease inhibitor of the NS3/4A gene of the hepatitis C virus (HCV). The US FDA has approved its use in conjunction with peginterferon-alfa and ribavirin to treat hepatitis B and C. It works directly against the hepatitis C virus. Japan has also approved the use of simeprevir for the management of genotype 1 chronic hepatitis C infection. With IC50<13 nM for all HCV NS3/4A enzymes (genotypes 1a, 1b, 2, 4, 5, and 6), it exhibits a medium inhibitory concentration; however, for genotype 3, its IC50 value is 37 nM.
| Targets |
HCV NS3/4A protease (Ki = 0.36 nM); HCV replication (EC50 = 7.8 nM); SARS-CoV-2 Mpro (IC50 = 9.6±2.3 μM); SARS-CoV-2 RdRp (IC50 = 5.5±0.2 μM)
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| ln Vitro |
Simeprevir has a medium inhibitory concentration (IC50) of less than 13 nM for all HCV NS3/4A enzymes tested, demonstrating strong inhibition on NS3/4A protease of genotypes 1a, 1b, 2, 4, 5, and 6. In contrast, genotype 3 has an IC50 of 37 nM. Also inhibiting the bilirubin transporters OATP1B1 and MRP2 in vitro is simeprevir. When compared to MRP2 (IC50 of about 10,000 nM), which is primarily a conjugated bilirubin transporter, it is a more potent inhibitor of OATP1B1 (IC50=720 nM), which is primarily responsible for transporting unconjugated bilirubin1].
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| ln Vivo |
Simeprevir has a rather lengthy in vivo absorption phase; it takes 4-6 hours for the maximum concentration (Cmax) to be reached. 99.9% of it is firmly attached to plasma proteins, primarily albumin. Following a single oral administration, the absolute bioavailability is 44%. Rats with a liver to blood ratio of 29:1 have a well-distributed liver. In preclinical studies, the ratio of liver to plasma concentration is 39 for humans, which is extremely high. With a ratio of 128 in the small intestine, the tissue/plasma AUC ratios are the highest. Plasma concentrations are higher than the EC99 at 8 hours and around the EC50 at 24 hours after dosing, while tissue simeprevir concentrations reach their peak values within 4 hours after dosing.Liver simeprevir concentrations can stay above the EC99 for up to 31 hours after dosing. When simeprevir is given with food, its AUC24h increases by 61%–69%. Thus, it is recommended to take simeprevir with food. Simeprevir is a P-glycoprotein substrate and inhibitor as well. Simeprevir is excreted by the biliary system after being metabolized by CYP3A4. It also inhibits cytochrome 3A4 in the gut, but not CYP3A4 in the liver[1].
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| Enzyme Assay |
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, the in vitro inhibitory activity of simeprevir against NS3/4A is ascertained. In summary, RetS1 substrate is added to NS3/4A after it has been preincubated for 10 minutes in the presence of TMC435350. Fluorescence is then continuously monitored for 20 minutes (excitation wavelength: 355 nm; emission wavelength: 500 nm). Substratum cleavage is reported as a percentage of cleavage observed in the vehicle control.
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| Cell Assay |
Huh7-Luc cells are plated in a 384-well plate at a density of 2,500 cells/well using Dulbecco's modified Eagles medium supplemented with 10% fetal calf serum. The cells are then cultured with serially diluted simeprevir (TMC435350) at various concentrations, with a final DMSO concentration of 0.5% in the absence of G418. Following a 72-hour incubation period, a ViewLux reader is used to measure the luciferase signal after Steady Lite reagent is added to the medium in a 1:1 ratio.
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| Animal Protocol |
Sprague-Dawley (SD) rats and cynomolgus monkeys
3 mg/kg Oral administration |
| References |
| Molecular Formula |
C38H47N5O7S2
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| Molecular Weight |
749.94
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| Exact Mass |
749.29
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| Elemental Analysis |
C, 60.86; H, 6.32; N, 9.34; O, 14.93; S, 8.55
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| CAS # |
923604-59-5
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| Related CAS # |
Simeprevir sodium;1241946-89-3;Simeprevir-13C,d3
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| Appearance |
Solid powder
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| SMILES |
CC1=C(C=CC2=C1N=C(C=C2O[C@@H]3C[C@@H]4[C@@H](C3)C(=O)N(CCCC/C=C\[C@@H]5C[C@]5(NC4=O)C(=O)NS(=O)(=O)C6CC6)C)C7=NC(=CS7)C(C)C)OC
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| InChi Key |
JTZZSQYMACOLNN-VDWJNHBNSA-N
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| InChi Code |
InChI=1S/C38H47N5O7S2/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H,41,44)(H,42,46)/b10-8-/t23-,24-,27-,28-,38-/m1/s1
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| Chemical Name |
(1R,4R,6S,7Z,15R,17R)-N-cyclopropylsulfonyl-17-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (3.33 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.43 mg/mL (1.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.43 mg/mL (1.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02250807 | Completed | Drug: Simeprevir Drug: Sofosbuvir |
Chronic Hepatitis C Genotype 4 Chronic Hepatitis C |
Janssen R&D Ireland | January 2015 | Phase 3 |
| NCT02512562 | Completed | Drug: Simeprevir Drug: ACH-3102 |
Chronic Hepatitis C | Alios Biopharma Inc. | July 31, 2015 | Phase 1 |
| NCT02404805 | Completed | Drug: Simeprevir Drug: dolutegravir |
HIV Hepatitis C |
University of Colorado, Denver | February 2016 | Not Applicable |
| NCT02268864 | Completed | Drug: Simeprevir Drug: Daclatasvir |
Hepatitis C, Chronic | Janssen-Cilag International NV | January 2015 | Phase 2 |
| NCT02253550 | Completed | Drug: Simeprevir Drug: Sofosbuvir |
Chronic Hepatitis C | Peter J. Ruane, M.D. | October 2014 | Phase 2 |
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