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Products are for research use only. Not for human use. We do not sell to patients.

Signaling Pathway

Simeprevir

HY-10241

(TMC435; TMC435350; TMC-435350)

Simeprevir
Simeprevir Chemical Structure

Simeprevir (TMC 435350) is a potent inhibitor of HCV NS3/4A protease (Ki = 0.36 nM) and viral replication (replicon EC50 = 7.8 nM).

Price and Availability of Simeprevir
Size Price Stock
5 mg $550 In-stock
10 mg $880 In-stock
50 mg $2640 In-stock
100 mg $4400 In-stock
>1000 mg Get quote
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Simeprevir Data Sheet

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Purity: 99.33%

Cell Cycle/DNA Damage

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Biological Activity of Simeprevir

TMC-435350 (TMC 435350; TMC 435; TMC-435350) is an inhibitor of NS3/4A protease, which plays an important role in HCV replication. Data from phase I and II clinical trials of TMC-435350 (TMC 435350; TMC 435; TMC-435350) to date have shown that this agent is well tolerated as a once-daily oral therapy and provides potent antiviral activity in HCV genotype 1-infected subjects, with restoration of liver enzymes and no evidence of viral breakthrough.

Clinical Information

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References on Simeprevir

1 . Lin TI, Lenz O, Fanning G, Verbinnen T, Delouvroy F, Scholliers A, Vermeiren K, Rosenquist A, Edlund M, Samuelsson B, Vrang L, de Kock H, Wigerinck P, Raboisson P, Simmen K.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.
Abstract
The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC(50)) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC(99) value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.

2 . Manns M, Reesink H, Berg T, Dusheiko G, Flisiak R, Marcellin P, Moreno C, Lenz O, Meyvisch P, Peeters M, Sekar V, Simmen K, Verloes R.Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial.Antivir Ther. 2011;16(7):1021-33.
Abstract
BACKGROUND: Antiviral activity of TMC435, an oral, once-daily, HCV NS3/4A protease inhibitor, was evaluated with pegylated interferon-α2a/ribavirin (P/R) in HCV genotype-1 patients. METHODS: Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA-1; TMC435-C201; NCT00561353) is a Phase IIa, randomized, placebo-controlled study. Treatment-naive patients (n=74) received 25, 75 or 200 mg TMC435 once daily, or placebo for 7 days followed by 21 days of triple therapy with P/R, or triple therapy for 28 days. Treatment-experienced patients (n=37; 56.8% with cirrhosis) received 75, 150 or 200 mg TMC435 once daily, or placebo with P/R for 28 days. Patients continued P/R up to week 48...

3 . Xue W, Pan D, Yang Y, Liu H, Yao X.Molecular modeling study on the resistance mechanism of HCV NS3/4A serine protease mutants R155K, A156V and D168A to TMC435.Antiviral Res. 2012 Jan;93(1):126-37. Epub 2011 Nov 22.
Abstract
Hepatitis C virus (HCV) NS3/4A protease represents an attractive drug target for antiviral therapy. However, drug resistance often occurs, making many protease inhibitors ineffective and allowing viral replication to occur. Herein, based on the recently determined structure of NS3/4A-TMC435 complex, atomic-level models of the key residue mutated (R155K, A156V and D168A) NS3/4A-TMC435 complexes were constructed. Subsequently, by using molecular dynamics simulations, binding free energy calculation and substrate envelope analysis, the structural and energetic changes responsible for drug resistance were investigated. The values of the calculated binding free energy follow consistently the order of the experimental activities. More importantly, the computational results demonstrate that R155K and D168A mutations break the intermolecular salt bridges network at the extended S2 subsite and affect the TMC435 binding, while A156V mutation leads to a significant steric clash with TMC435 and further disrupts the two canonical substrate-like intermolecular hydrogen bond interactions (TMC435(N1-H46)?Arg155(O) and Ala157(N-H)?TMC435(O2)). In addition, by structural analysis, all the three key residue mutations occur outside the substrate envelope and selectively weaken TMC435's binding affinity without effect on its natural substrate peptide (4B5A). These findings could provide some insights into the resistance mechanism of NS3/4A protease mutants to TMC435 and would be critical for the development of novel inhibitors that are less susceptible to drug resistance.

4 . Lin, Tse-I.; Lenz, Oliver; Fanning, Gregory; Verbinnen, Thierry; Delouvroy, Frederic; In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrobial Agents and Chemotherapy (2009), 53(4), 1377-1385.
Abstract
The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC50) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replic...

5 . Raboisson, Pierre; de Kock, Herman; Rosenquist, Asa; 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. Bioorganic & Medicinal Chemistry Letters (2008), 18(17), 4853-4858.
Abstract
SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4Aprotease (Ki?=?0.36?nM) and viral replication (replicon EC50?=?7.8?nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics....

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