| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Faldaprevir (BI 201335) targets the HCV NS3 protease (genotype 1b). In an enzymatic assay using genotype 1b NS3-NS4A enzyme and a fluorogenic depsipeptide substrate, the compound exhibited an IC50 of 3 nM. [1]
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|---|---|
| ln Vitro |
In a cell-based bicistronic luciferase reporter replicon assay (genotype 1b), Faldaprevir (BI 201335) demonstrated an EC50 of 3 nM. [1]
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| ln Vivo |
In a Phase Ib clinical trial (SOUND-C1) in treatment-naive patients with chronic HCV genotype 1 infection, a regimen consisting of Faldaprevir (BI 201335) 120 mg once daily, deleobuvir (BI 207127) 600 mg three times daily, and weight-based ribavirin for 4 weeks, followed by response-guided faldaprevir plus pegylated interferon-α2a/ribavirin, achieved a sustained virological response 24 weeks after completion of treatment (SVR24) rate of 94% (16/17 patients). [2]
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| Enzyme Assay |
Biochemical assays were carried out using 0.5 µM genotype 1b NS3-NS4A enzyme and a fluorogenic depsipeptide substrate (anthranilyl-DDIVPAbu[CO-O]AMY(3-NO2)-TW-OH). The reaction buffer consisted of 50 mM Tris-HCl (pH 8.0), 0.25 M sodium citrate, 0.01% n-dodecyl-β-D-maltoside, 1 mM TCEP, and 5% DMSO. Mixtures were incubated at 23°C for 60-70 minutes and terminated by the addition of 1 M MES (pH 5.8). Fluorescence of the N-terminal product (anthranilyl-DDIVP-Abu) was measured using a plate reader. Percent inhibition at each inhibitor concentration was used to determine the median effective concentration (IC50). [1]
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| Cell Assay |
The cell-based replicon assay used a bicistronic luciferase reporter replicon encoding the Con1 genotype 1b NS2-NS5B coding region. Compounds were incubated with cells for 72 hours. The relative levels of luciferase present were determined using a luciferase substrate on a Top-count instrument. EC50 values were determined by nonlinear regression. [1]
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| Animal Protocol |
For oral pharmacokinetic studies, male Sprague-Dawley rats (275-300 g) were fasted overnight with access to 10% dextrose in water. An oral dose of 5 mg/kg of Faldaprevir (BI 201335) was administered in a dosing volume of 10 mL/kg of a vehicle consisting of 0.5% Methocel and 0.3% Tween-80. For intravenous pharmacokinetic experiments, a dose of 2 mg/kg was administered. Blood samples were collected from the cannulated right carotid at various time points post-dosing (0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours for oral; with an additional 5-minute sample for intravenous). Plasma samples from three rats were pooled at each time point. [1]
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| ADME/Pharmacokinetics |
Faldaprevir (BI 201335) (compound 29) was evaluated in rats. After an oral dose of 5 mg/kg, it achieved a maximum plasma concentration (Cmax) of 0.60 µM and an AUC0→∞ of 1.7 µM·h. After an intravenous dose of 2 mg/kg, it exhibited a half-life (T1/2) of 1.2 hours, a clearance (Cl) of 20 (mL/min)/kg, and a volume of distribution (Vss) of 1.9 L/kg. The overall oral bioavailability (F) in rats was 40%. The compound partitions favorably into the liver in rats with a 40-fold increase in liver versus plasma concentration after oral dosing. It was stable in human (T1/2 > 100 min) and rat liver microsomes (T1/2 > 300 min). [1]
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| Toxicity/Toxicokinetics |
In the SOUND-C1 clinical trial, during the 4-week interferon-free treatment phase with Faldaprevir (BI 201335), deleobuvir, and ribavirin, there were no severe or serious adverse events and no premature treatment discontinuations due to adverse events. The most common adverse events during this period were mild-to-moderate nausea (47%), vomiting (38%), diarrhoea (22%), asthenia (28%), pruritus (28%), rash (16%), and photosensitivity (19%). One patient experienced anaemia requiring ribavirin dose reduction. During the subsequent faldaprevir plus pegylated interferon-α2a/ribavirin treatment phase, the most common adverse events were pruritus (38%), rash (31%), and asthenia (31%); these were severe in approximately 3% of patients. Three patients discontinued all drugs due to severe adverse events: pancytopenia; eczema and pruritus; and maculopapular rash, pruritus, and eye swelling. Effects on bilirubin were mainly via an increase in the indirect fraction and were not associated with increases in alanine aminotransferase or clinical signs of liver dysfunction. [2]
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| References |
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| Additional Infomation |
Faldaprevir (BI 201335) is a noncovalent linear inhibitor of the HCV NS3 protease, a class of inhibitors that have only ionic interactions with the catalytic site on the NS3 protease. This mechanism is unusual among serine proteases and imparts selectivity. The compound was discovered through optimization of linear tripeptide inhibitors, where the introduction of a C8-bromo substituent on the quinoline moiety was found to be optimal for improving both cell-based potency and pharmacokinetic profile. In preclinical studies, it was stable in human and rat liver microsomes. In the SOUND-C1 trial, the combination of faldaprevir, deleobuvir, and ribavirin for 4 weeks followed by response-guided therapy demonstrated potent antiviral activity, with a 94% SVR24 rate in the deleobuvir 600 mg group. Patients who experienced viral breakthrough during the interferon-free phase were successfully treated with the subsequent interferon-containing regimen. [1][2]
|
| Molecular Formula |
C40H48BRN6NAO9S
|
|---|---|
| Molecular Weight |
891.80269908905
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| CAS # |
1215856-44-2
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| PubChem CID |
56594927
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| Appearance |
Typically exists as solids at room temperature
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| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
12
|
| Rotatable Bond Count |
15
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| Heavy Atom Count |
58
|
| Complexity |
1540
|
| Defined Atom Stereocenter Count |
5
|
| SMILES |
BrC1=C(C=CC2C1=NC(C1=CSC(NC(C(C)C)=O)=N1)=CC=2O[C@H]1CN(C([C@H](C(C)(C)C)NC(=O)OC2CCCC2)=O)[C@@H](C1)C(N[C@]1(C(=O)[O-])C[C@H]1C=C)=O)OC.[Na+]
|
| Synonyms |
BI 201335 sodium
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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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1213 mL | 5.6066 mL | 11.2133 mL | |
| 5 mM | 0.2243 mL | 1.1213 mL | 2.2427 mL | |
| 10 mM | 0.1121 mL | 0.5607 mL | 1.1213 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.
A phase III, randomised, double-blind and placebo-controlled study of once daily BI 201335 120 mg for 12 or 24 weeks or BI 201335 240 mg for 12 weeks in combination with pegylated interferon-α and ribavirin in treatment-naïve patients with genotype 1 chronic hepatitis C infection
CTID: null
Phase: Phase 3 Status: Completed
Date: 2011-03-11
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