Beclabuvir (BMS-791325)
(Synonyms: BMS-791325) 目录号 : GC33925
Beclabuvir (BMS-791325) 是一种变构抑制剂，可与丙型肝炎病毒 (HCV) NS5B RNA 依赖性 RNA 聚合酶的拇指位点 1 结合，并抑制来自 HCV 基因型 1、3、4 和 5 的重组 NS5B 蛋白，IC50 为< 28 海里。
Cas No.:958002-33-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Beclabuvir is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, and inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 with IC50 of < 28 nM.
Beclabuvir demonstrates additive or synergistic antiviral activity with pegIFN/RBV and in 2- or 3-drug combinations with a range of DAAs, such as HCV NS3 protease inhibitors, NS5A inhibitors' and/or nucleoside NS5B inhibitors[2].
The combination of beclabuvir with asunaprevir and daclatasvir achieves very high rates of viral eradication (about 90%) in patients infected with HCV genotype 1, which is the most common genotype worldwide[1].
[1]. Gentile I, et al. Beclabuvir for the treatment of hepatitis C. Expert Opin Investig Drugs. 2015;24(8):1111-21. [2]. Tatum H, et al. A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1. J Viral Hepat. 2015 Aug;22(8):658-64.
| Cas No. | 958002-33-0 | SDF | |
| 别名 | BMS-791325 | ||
| Canonical SMILES | O=C(N1C2CCC1CN(C)C2)[C@@]3(CN4C5=C(C6CCCCC6)C7=CC=C(C(NS(N(C)C)(=O)=O)=O)C=C47)[C@H](C8=CC(OC)=CC=C85)C3 | ||
| 分子式 | C36H45N5O5S | 分子量 | 659.84 |
| 溶解度 | DMSO : ≥ 30 mg/mL (45.47 mM) | 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 | 1.5155 mL | 7.5776 mL | 15.1552 mL |
| 5 mM | 0.3031 mL | 1.5155 mL | 3.031 mL |
| 10 mM | 0.1516 mL | 0.7578 mL | 1.5155 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。
Beclabuvir for the treatment of hepatitis C
Expert Opin Investig Drugs 2015;24(8):1111-21.PMID:26156630DOI:10.1517/13543784.2015.1059820.
Introduction: About 185,000,000 people worldwide are chronically infected with hepatitis C virus (HCV). Currently, the most successful HCV infection antiviral therapies reduce the chance of progression towards the advanced phases of the hepatopathy (liver cirrhosis, hepatocellular carcinoma and death). Recently, however, several new direct-acting antivirals against HCV are available or are in an advanced phase of clinical development. Areas covered: This review focuses on Beclabuvir , an allosteric non-nucleotide inhibitor of HCV polymerase. The article covers its pharmacokinetics, mechanism of action, in addition to its tolerability and safety profile as well as its resistance pattern. Expert opinion: The pharmacokinetic, efficacy and tolerability profile of Beclabuvir, as well as its barrier to resistance, are very favorable. In particular, the combination of Beclabuvir with asunaprevir and daclatasvir achieves very high rates of viral eradication (about 90%) in patients infected with HCV genotype 1, which is the most common genotype worldwide. Therefore, Beclabuvir represents a powerful weapon against HCV infection and has to be considered an optimal option in tailored IFN-free combinations.
Preclinical characterization of BMS-791325, an allosteric inhibitor of hepatitis C Virus NS5B polymerase
Antimicrob Agents Chemother 2014 Jun;58(6):3485-95.PMID:24733465DOI:10.1128/AAC.02495-13.
BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 μM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥ 10-fold above the inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.
Mechanism of inhibition for BMS-791325, a novel non-nucleoside inhibitor of hepatitis C virus NS5B polymerase
J Biol Chem 2014 Nov 28;289(48):33456-68.PMID:25301950DOI:10.1074/jbc.M114.613653.
HCV infection is an urgent global health problem that has triggered a drive to discover therapies that specifically target the virus. BMS-791325 is a novel direct antiviral agent specifically targeting HCV NS5B, an RNA-dependent RNA polymerase. Robust viral clearance of HCV was observed in infected patients treated with BMS-791325 in combination with other anti-HCV agents in Phase 2 clinical studies. Biochemical and biophysical studies revealed that BMS-791325 is a time-dependent, non-competitive inhibitor of the polymerase. Binding studies with NS5B genetic variants (WT, L30S, and P495L) exposed a two-step, slow binding mechanism, but details of the binding mechanism differed for each of the polymerase variants. For the clinically relevant resistance variant (P495L), the rate of initial complex formation and dissociation is similar to WT, but the kinetics of the second step is significantly faster, showing that this variant impacts the final tight complex. The resulting shortened residence time translates into the observed decrease in inhibitor potency. The L30S variant has a significantly different profile. The rate of initial complex formation and dissociation is 7-10 times faster for the L30S variant compared with WT; however, the forward and reverse rates to form the final complex are not significantly different. The impact of the L30S variant on the inhibition profile and binding kinetics of BMS-791325 provides experimental evidence for the dynamic interaction of fingers and thumb domains in an environment that supports the formation of active replication complexes and the initiation of RNA synthesis.
Potency and resistance analysis of hepatitis C virus NS5B polymerase inhibitor BMS-791325 on all major genotypes
Antimicrob Agents Chemother 2014 Dec;58(12):7416-23.PMID:25267677DOI:10.1128/AAC.03851-14.
BMS-791325 is a hepatitis C virus (HCV) inhibitor binding to the thumb domain of the NS5B RNA-dependent RNA polymerase. BMS-791325 is well characterized in genotype 1 (GT1) and exhibits good inhibitory activity (50% effective concentration [EC50], <10 nM) against hybrid replicons containing patient NS5B sequences from GT3a, -4a, and -5a while potency against GT2 is significantly reduced (J. A. Lemm et al., Antimicrob. Agents Chemother. 58:3485-3495, 2014, doi:http://dx.doi.org/10.1128/AAC.02495-13). BMS-791325 potency against GT6a hybrid replicons is more variable, with two of three hybrid clones having EC50s similar to that for GT1 while a third patient clone was ∼ 10 times less susceptible to BMS-791325. To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a and -3a to -6a and demonstrated that GT1a has the highest resistance barrier versus BMS-791325 while GT6a has the lowest. Selection of GT3 to -6 NS5B chimeric replicon cells at different concentrations of BMS-791325 revealed substitutions in the thumb domain of NS5B at residues 494 and 495 that conferred different levels of resistance to BMS-791325 but remained susceptible to NS5A or NS3 protease inhibitors. In addition, we demonstrate that the reduced potency of BMS-791325 against one GT6a patient is due to an A494 polymorphism present in ∼ 21% of sequences in the European HCV database. The results from this report suggest that BMS-791325 is a candidate for combination treatment of HCV GT3 to -6 chronic infections, and the resistance profiles identified will provide useful information for future clinical development.
Optimal therapy in genotype 4 chronic hepatitis C: finally cured?
Liver Int 2015 Jan;35 Suppl 1:27-34.PMID:25529085DOI:10.1111/liv.12724.
Optimal therapy for patients with hepatitis C virus (HCV) genotype 4 (HCV-4) infection is changing rapidly, and the possibility of a total cure is near. The standard of care has been combination pegylated interferon (PEG-IFN)-ribavirin (RBV), with modest response rates and considerable adverse events. Since the introduction of sofosbuvir (SOF), simeprevir (SIM), and daclatasvir (DCV), the duration of treatment has been significantly shortened and response rates have increased. The recommended treatment for IFN-eligible patients is PEG-IFN/RBV plus SOF, SIM or DCV. In IFN ineligible patients, the optimal regimen is a 24-week course of SOF/RBV, or a 12-week course of SOF-SIM or SOF-DCV with or without RBV. The pipeline for patients with chronic HCV is highly active. IFN-free combinations with paritaprevir-ombitasvir, SOF-ledipasvir, or DCV-asunaprevir (ASV)-beclabuvir (BMS-791325) for 12 weeks or less with close to 100% cure rates will soon become the optimal therapy.