Filibuvir
(Synonyms: (R)-6-环戊基-6-[2-(2,6-二乙基吡啶-4-基)乙基]-3-[(5,7-二甲基-[1,2,4]三唑并[1,5-A]嘧啶-2-基)甲基]-4-羟基-5,6-二氢-2H-吡喃-2-酮) 目录号 : GC36045
Filibuvir 是 HCV 非结构性 5B 蛋白 (NS5B) RNA 依赖性的 RNA 聚合酶的有效选择性非核苷抑制剂 (NNI)，它在 NS5B 的 “Thumb 2” 口袋中非共价结合。 在体外，filibuvir 与基因型 1 a 和 1 b 复制子等效，EC50 为 59 nM。
Cas No.:877130-28-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Filibuvir is a potent, selective non-nucleoside inhibitor (NNI) of the HCV nonstructural 5B protein (NS5B) RNA-dependent RNA polymerase, and it binds noncovalently in the "Thumb 2" pocket of NS5B. In vitro, filibuvir is equipotent against genotype 1a and 1b replicons, with an EC50 of 59 nM[1].
[1]. Wagner F, et al. Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients. Hepatology. 2011 Jul;54(1):50-9.
| Cas No. | 877130-28-4 | SDF | |
| 别名 | (R)-6-环戊基-6-[2-(2,6-二乙基吡啶-4-基)乙基]-3-[(5,7-二甲基-[1,2,4]三唑并[1,5-A]嘧啶-2-基)甲基]-4-羟基-5,6-二氢-2H-吡喃-2-酮 | ||
| Canonical SMILES | O=C(O1)C(CC2=NN(C(C)=C3)C(N=C3C)=N2)=C(O)C[C@@]1(C4CCCC4)CCC5=CC(CC)=NC(CC)=C5 | ||
| 分子式 | C29H37N5O3 | 分子量 | 503.64 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9855 mL | 9.9277 mL | 19.8555 mL |
| 5 mM | 0.3971 mL | 1.9855 mL | 3.9711 mL |
| 10 mM | 0.1986 mL | 0.9928 mL | 1.9855 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Filibuvir, a non-nucleoside NS5B polymerase inhibitor for the potential oral treatment of chronic HCV infection
IDrugs 2010 Dec;13(12):938-48.PMID:21154154doi
Filibuvir (PF-868554), being developed by Pfizer, is an orally administered, non-nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase for the potential treatment of chronic HCV infection. An estimated 180 million people worldwide are infected with HCV and at risk of developing chronic liver diseases that can lead to cirrhosis or hepatocellular carcinomas. HCV infection is the main cause of liver transplantation in industrialized nations. Filibuvir is a potent and specific inhibitor of the virally-encoded NS5B polymerase, and inhibited genotype 1 subgenomic HCV replication in the cell-based replicon system. Filibuvir demonstrated a good pharmacokinetic profile and oral bioavailability in preclinical animal studies, which is consistent with twice-daily dosing in humans. In phase I and a IIa clinical trial in treatment-naïve patients infected with genotype 1 HCV, Filibuvir monotherapy or in combination with pegylated IFNα2a/ribavirin (the standard of care [SoC] for HCV infection) for up to 4 weeks significantly reduced HCV RNA levels compared with placebo or SoC alone. The incidence and severity of adverse events were similar to SoC and placebo. At the time of publication, phase I pharmacokinetic clinical trials were ongoing in healthy volunteers and a phase IIb clinical trial was assessing Filibuvir in combination with SoC for up to 24 weeks in treatment-naïve patients infected with genotype 1 HCV. Results of this trial will help to characterize the potential of this drug class for the treatment of HCV infections.
A phase 2 study of Filibuvir in combination with pegylated IFN alfa and ribavirin for chronic HCV
Ann Hepatol 2014 Jul-Aug;13(4):364-75.PMID:24927607doi
Objectives: Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evaluated the safety and efficacy of Filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin. Material and methods: Treatment-naïve, HCV genotype-1 patients were randomized to receive Filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 μg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibuvir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the proportion of patients who achieved sustained virologic response (SVR) defined as HCV RNA < 15 IU/mL at end of treatment (weeks 24 or 48) and week 72. Results: Overall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the Filibuvir 300 mg, 600 mg, and placebo arms, respectively. While the addition of Filibuvir to pegIFN/ribavirin improved on-treatment virologic response parameters, this did not translate into improved SVR rates due to a high rate of virologic relapse following completion of therapy (300 mg: 35.9%; 600 mg: 42.9%; placebo: 25.4%). The most commonly reported adverse events were nausea, fatigue, headache, and insomnia, and were reported at similar rates across arms. Conclusions: Filibuvir plus pegIFN/ribavirin did not improve the percentage of patients achieving SVR compared with administration of pegIFN/ribavirin alone. However, the agent was well tolerated and was associated with higher on-treatment virologic response parameters. Further evaluation of Filibuvir in combination with other direct-acting antiviral agents may be considered.
Characterization of resistance to the nonnucleoside NS5B inhibitor Filibuvir in hepatitis C virus-infected patients
Antimicrob Agents Chemother 2012 Mar;56(3):1331-41.PMID:22203605DOI:10.1128/AAC.05611-11.
Filibuvir (PF-00868554) is an investigational nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural 5B (NS5B) RNA-dependent RNA polymerase currently in development for treating chronic HCV infection. The aim of this study was to characterize the selection of filibuvir-resistant variants in HCV-infected individuals receiving Filibuvir as short (3- to 10-day) monotherapy. We identified amino acid M423 as the primary site of mutation arising upon Filibuvir dosing. Through bulk cloning of clinical NS5B sequences into a transient-replicon system, and supported by site-directed mutagenesis of the Con1 replicon, we confirmed that mutations M423I/T/V mediate phenotypic resistance. Selection in patients of an NS5B mutation at M423 was associated with a reduced replicative capacity in vitro relative to the pretherapy sequence; consistent with this, reversion to wild-type M423 was observed in the majority of patients following therapy cessation. Mutations at NS5B residues R422 and M426 were detected in a small number of patients at baseline or the end of therapy and also mediate reductions in Filibuvir susceptibility, suggesting these are rare but clinically relevant alternative resistance pathways. Amino acid variants at position M423 in HCV NS5B polymerase are the preferred pathway for selection of viral resistance to Filibuvir in vivo.
Antiviral activity of the hepatitis C virus polymerase inhibitor Filibuvir in genotype 1-infected patients
Hepatology 2011 Jul;54(1):50-9.PMID:21488067DOI:10.1002/hep.24342.
More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor Filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of Filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The Filibuvir doses evaluated ranged from 200-1400 mg daily, and the duration of dosing ranged from 3-10 days. Genotypic changes in the NS5B nucleotide sequence following short-term Filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from -0.97 log(10) IU/mL with Filibuvir given at 100 mg twice daily to -2.30 log(10) IU/mL with Filibuvir given at 700 mg twice daily in treatment-naive patients. In treatment-experienced patients, an HCV RNA reduction of 2.20 log(10) IU/mL was achieved with Filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after Filibuvir dosing. Conclusion: Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients.
Determination and control of TEMPO, a potentially genotoxic free radical reagent used in the synthesis of Filibuvir
J Pharm Biomed Anal 2012 Mar 25;62:216-9.PMID:22269174DOI:10.1016/j.jpba.2011.12.036.
The synthesis of Filibuvir, a hepatitis C virus polymerase inhibitor candidate, involves use of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a potentially genotoxic free radical reagent. A headspace gas chromatographic method utilizing selected-ion monitoring (SIM) mode mass spectrometric detection was developed, validated and applied to the determination of low levels of TEMPO in Filibuvir. The GC-MS method was validated in terms of specificity, linearity, precision, accuracy/recovery, limit of quantitation (LOQ) and limit of detection (LOD). The method was shown to be specific for detection of TEMPO in the presence of Filibuvir and exhibited acceptable linearity (r ≥ 0.997) over the range of 4-60 ppm vs. Filibuvir (0.4-6.0 μg/mL). The system precision was 14% and 8% relative standard deviation (RSD) at the 4 ppm and 8 ppm levels, respectively. Method repeatability was 15% and 13% RSD at the 4 ppm and 8 ppm levels, respectively. Recovery was approximately 50-80% across the method range. Accuracy was 135% and 91% vs. nominal at the 4 and 8 ppm levels, respectively. The LOQ and LOD are 4 ppm and 2 ppm, respectively. Thirteen batches of Filibuvir drug substance had no detectable TEMPO (≤ 2 ppm). Purge studies demonstrated that the synthetic process has an extremely high capability to remove TEMPO and consistently delivers Filibuvir drug substance with TEMPO levels well below the staged threshold of toxicological concern.