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| 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]
- Enzymatic Activity: As a noncovalent inhibitor, Faldaprevir potently binds and inhibits the HCV NS3/4A protease, with Ki values of 2.0 nM (GT1b) and 2.6 nM (GT1a). - Antiviral Activity: In Huh-7 cells, Faldaprevir effectively inhibits HCV RNA replication. The half-maximal effective concentrations (EC50) are 3.1 nM for genotype 1b and 6.5 nM for genotype 1a. It also shows activity against genotype 2a, with EC50 values of approximately 43 to 50 nM. - Cytotoxicity: The half-maximal cytotoxic concentration (CC50) in Huh-7 cells is 30,000 nM, indicating a high selectivity index. - Metabolic Stability & Transport: Faldaprevir is metabolized in vitro primarily by CYP3A4/5 in the liver to form monohydroxylated metabolites M2a and M2b. These metabolites are substrates for the efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). |
| 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]
- Clinical Efficacy: In a Phase 2 trial (SILEN-C3) for treatment-naive HCV GT1 patients, Faldaprevir (120 mg once daily) combined with PegIFN/RBV achieved high sustained virologic response (SVR) rates of 67% (12-week faldaprevir group) and 74% (24-week faldaprevir group). - Hyperbilirubinemia Mechanism: In monkeys and clinical studies, faldaprevir causes reversible, unconjugated hyperbilirubinemia, primarily through competitive inhibition of UGT1A1 (bilirubin conjugation) and OATP1B1/1B3 (bilirubin uptake). |
| 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]
- Protease Inhibition Assay: Recombinant HCV NS3/4A protease is incubated with a fluorogenic peptide substrate and serial dilutions of faldaprevir. The inhibition of protease activity is measured by a decrease in fluorescence signal, and the Ki value is calculated. - Reaction Phenotyping: Faldaprevir is incubated with recombinant human CYP450 enzymes (e.g., CYP3A4/5) or human hepatocytes. The formation of metabolites (M2a and M2b) is analyzed by LC-MS to identify the primary enzymes responsible for its metabolism. - Transporter Studies: Transport assays are performed using cell lines overexpressing specific transporters like P-gp, BCRP, OATP1B1, OATP1B3, or MRP2. The uptake or efflux of faldaprevir or its metabolites is measured to assess interaction and calculate IC50 values. |
| 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]
- Antiviral Activity (Replicon Assay): Huh-7 cells harboring an HCV subgenomic replicon are incubated with various concentrations of faldaprevir for 72 hours. HCV RNA levels are measured by RT-PCR, or luciferase activity is measured, to determine the EC50 for inhibition of viral replication. - Cytotoxicity Assay: Huh-7 cells are treated with a range of faldaprevir concentrations. Cell viability is assessed using an MTT assay to calculate the CC50. |
| 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]
- Rat PK and Distribution Study: Rats receive a single oral (10 mg/kg) or intravenous (2 mg/kg) dose of [¹⁴C]-labeled faldaprevir. Blood, tissues, urine, and feces are collected at predetermined time points. Radioactivity is measured by liquid scintillation counting, and metabolites are identified by LC-MS. - Monkey Hyperbilirubinemia Study: Monkeys are administered faldaprevir orally (≥20 mg/kg per day). Blood samples are drawn periodically to measure serum levels of total, direct, and indirect bilirubin to assess the drug's effect on bilirubin clearance. |
| 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]
- Human PK: In healthy subjects, faldaprevir is slowly absorbed. After single doses (4-1200 mg), the median tmax ranges from 4.0 to 14.0 hours, and the geometric mean terminal t1/2 ranges from 15.5 to 39.2 hours. Exposure (Cmax and AUC) increases in a more than dose-proportional manner. Urinary excretion of unchanged drug is less than 0.1% of the dose. A high-fat meal increases its relative bioavailability by 14%. - Rat PK: Following oral administration in rats, radioactivity is rapidly distributed to tissues, with the highest levels in the liver, lung, kidney, and adrenal gland. Plasma clearance (CL) is approximately 18 mL/min/kg. - Metabolism & Excretion: Faldaprevir is primarily eliminated via the hepatobiliary route. In rats, > 90% of the radioactive dose is recovered in feces, with <1.1% in urine. In humans, excretion is almost exclusively fecal (98.7%), with negligible urinary excretion (0.11%). Unchanged faldaprevir accounts for 52% of fecal radioactivity, while monohydroxylated metabolites M2a and M2b account for 41%. |
| 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]
- Hyperbilirubinemia: The most notable adverse effect is reversible, unconjugated hyperbilirubinemia, which is clinically benign and not associated with hepatotoxicity. It results from competitive inhibition of UGT1A1, OATP1B1, and OATP1B3. - Safety Summary: Faldaprevir is generally well-tolerated. In clinical trials combining it with PegIFN/RBV, approximately 6% of patients discontinued treatment due to adverse events. Most adverse events were mild or moderate in severity. |
| 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]
Faldaprevir has been investigated for the treatment of chronic hepatitis C. Drug Indications Treatment of chronic viral hepatitis C |
| Molecular Formula |
C40H49BRN6O9S
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|---|---|
| Molecular Weight |
869.829
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| Exact Mass |
868.246
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| Elemental Analysis |
C, 55.23; H, 5.68; Br, 9.19; N, 9.66; O, 16.55; S, 3.69
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| CAS # |
801283-95-4
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| Related CAS # |
Faldaprevir-d6;2750534-88-2; 1215856-44-2; Faldaprevir-d7;1613250-18-2
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| PubChem CID |
42601552
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| Appearance |
Solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.647
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| LogP |
5.34
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
15
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| Heavy Atom Count |
57
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| Complexity |
1530
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| Defined Atom Stereocenter Count |
5
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| SMILES |
N([C@@]1(C[C@H]1C=C)C(=O)O)C([C@@H]1C[C@@H](OC2C=C(C3=CSC(NC(=O)C(C)C)=N3)N=C3C(=C(C=CC=23)OC)Br)CN1C(=O)[C@H](C(C)(C)C)NC(=O)OC1CCCC1)=O
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| InChi Key |
LLGDPTDZOVKFDU-XUHJSTDZSA-N
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| InChi Code |
InChI=1S/C40H49BrN6O9S/c1-8-21-17-40(21,36(51)52)46-34(49)27-15-23(18-47(27)35(50)32(39(4,5)6)44-38(53)56-22-11-9-10-12-22)55-29-16-25(26-19-57-37(43-26)45-33(48)20(2)3)42-31-24(29)13-14-28(54-7)30(31)41/h8,13-14,16,19-23,27,32H,1,9-12,15,17-18H2,2-7H3,(H,44,53)(H,46,49)(H,51,52)(H,43,45,48)/t21-,23-,27+,32-,40-/m1/s1
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| Chemical Name |
(1R,2S)-1-((2S,4R)-4-((8-bromo-2-(2-isobutyramidothiazol-4-yl)-7-methoxyquinolin-4-yl)oxy)-1-((S)-2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-2-vinylcyclopropane-1-carboxylic acid
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| Synonyms |
BI 201335; BI201335; Faldaprevir; 801283-95-4; BI-201,335; 958X4J301A; (1R,2S)-1-((2S,4R)-4-(8-bromo-2-(2-isobutyramidothiazol-4-yl)-7-methoxyquinolin-4-yloxy)-1-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylic acid; BI-201335;
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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)
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| Solubility (In Vitro) |
DMSO: ~2 mg/mL (2.3 mM)
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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 | 1.1496 mL | 5.7482 mL | 11.4965 mL | |
| 5 mM | 0.2299 mL | 1.1496 mL | 2.2993 mL | |
| 10 mM | 0.1150 mL | 0.5748 mL | 1.1496 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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