Simeprevir

Modify Date: 2024-01-02 17:32:49

Simeprevir Structure
Simeprevir structure
 Common Name Simeprevir
CAS Number 923604-59-5 Molecular Weight 749.939
Density 1.4±0.1 g/cm3 Boiling Point N/A
Molecular Formula C38H47N5O7S2 Melting Point N/A
MSDS N/A Flash Point N/A

 Use of Simeprevir


Simeprevir is a potent HCV NS3/4A protease inhibitor which suppresses HCV replication with EC50 of 8 nM.

 Names

Name Simeprevir
Synonym More Synonyms

 Simeprevir Biological Activity

Description Simeprevir is a potent HCV NS3/4A protease inhibitor which suppresses HCV replication with EC50 of 8 nM.
Related Catalog
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].
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.
Cell Assay 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.
Animal Admin 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.
References

[1]. Lin TI, et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.Antimicrob Agents Chemother. 2009 Apr;53(4):1377-85. Epub 2009 Jan 26.

[2]. Raboisson P, et al. Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8.

[3]. Zhang X, et al. Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism. Eur J Med Chem. 2018 Jan 1;143:1053-1065.

 Chemical & Physical Properties

Density 1.4±0.1 g/cm3
Molecular Formula C38H47N5O7S2
Molecular Weight 749.939
Exact Mass 749.291687
PSA 193.51000
LogP 4.99
Index of Refraction 1.653
Storage condition 2-8°C

 Synonyms

(2R,11aS,12aR,14aR,Z)-N-(cyclopropylsulfonyl)-2-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)-5-methyl-4,14-dioxo-1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a-hexadecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a-carboxamide
Simeprevir
TMC435350
TMC-435350
Cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide, N-(cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, (2R,3aR,10Z,11aS,12aR,14aR)-
Olysio
(2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2-{[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy}-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide
Olysio (TN)
(2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide
TMC435
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Related Compounds: More...
Simeprevir sodium
1241946-89-3
simeprevir intermediate
1425704-76-2
Chemsrc provides Simeprevir(CAS#:923604-59-5) MSDS, density, melting point, boiling point, structure, formula, molecular weight etc. Articles of Simeprevir are included as well.>> amp version: Simeprevir

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