Entecavir (BMS200475)
(Synonyms: 恩替卡韦; BMS200475; SQ34676) 目录号 : GC32093
An antiviral nucleoside analog
Cas No.:142217-69-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | BMS 200475 is prepared in phosphate-buffered saline (PBS) and diluted with appropriate medium containing 2% fetal bovine serum. HepG2 2.2.15 cells are plated at a density of 5×105 cells per well on 12-well Biocoat collagen-coated plates and are maintained in a confluent state for 2 to 3 days before being overlaid with 1 mL of medium spiked with BMS 200475. Quantification of HBV was performed on day 10[1]. |
References: [1]. Innaimo SF, et al. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus. Antimicrob Agents Chemother. 1997 Jul;41(7):1444-9. | |
Entecavir is an antiviral nucleoside analog of 2'-deoxyguanosine and inhibitor of hepatitis B virus (HBV) reverse transcriptase (IC50 = 0.5 nM).1,2 It undergoes phosphorylation by cellular kinases to its active form, entecavir triphosphate.3,2 Entecavir reduces virion DNA in the culture supernatant of HepG2 2.2.15 cells infected with hepatitis B virus (HBV; EC50 = 3.75 nM).1 It reduces serum and hepatic levels of viral DNA in a duckling model of HBV infection when administered at a dose of 1 mg/kg.4 Formulations containing entecavir have been used in the treatment of chronic HBV infection.
1.Innaimo, S.F., Seifer, M., Bisacchi, G.S., et al.Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virusAntimicrob. Agents Chemother.41(7)1444-1448(1997) 2.Langley, D.R., Walsh, A.W., Baldick, C.J., et al.Inhibition of hepatitis B virus polymerase by entecavirJ. Virol.81(8)3992-4001(2007) 3.Fung, J., Lai, C.-L., Seto, W.-K., et al.Nucleoside/nucleotide analogues in the treatment of chronic hepatitis BJ. Antimicrob. Chemother.66(12)2715-2725(2011) 4.Marion, P.L., Salazar, F.H., Winters, M.A., et al.Potent efficacy of entecavir (BMS-200475) in a duck model of hepatitis B virus replicationAntimicrob. Agents Chemother.46(1)82-88(2002)
| Cas No. | 142217-69-4 | SDF | |
| 别名 | 恩替卡韦; BMS200475; SQ34676 | ||
| Canonical SMILES | O=C1NC(N)=NC2=C1N=CN2[C@@H]3C([C@H](CO)[C@@H](O)C3)=C | ||
| 分子式 | C12H15N5O3 | 分子量 | 277.28 |
| 溶解度 | DMSO : ≥ 44 mg/mL (158.68 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 | 3.6065 mL | 18.0323 mL | 36.0646 mL |
| 5 mM | 0.7213 mL | 3.6065 mL | 7.2129 mL |
| 10 mM | 0.3606 mL | 1.8032 mL | 3.6065 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。
Total synthesis of Entecavir
J Org Chem 2013 Jun 7;78(11):5482-91.PMID:23678976DOI:10.1021/jo400607v.
Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron-aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl-catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.
A review of Entecavir in the treatment of chronic hepatitis B infection
Curr Med Res Opin 2005 Nov;21(11):1845-56.PMID:16307706DOI:10.1185/030079905X65268.
Background: Infection with the hepatitis B virus (HBV) affects two billion people worldwide, and an estimated 400 million people are chronically infected. Currently, FDA-approved regimens for the treatment of chronic HBV include interferon-alpha2b, peginterferon-alpha2a, lamivudine, adefovir dipivoxil, and recently, Entecavir. Objective: The purpose of this review is to evaluate the pharmacokinetic and pharmacodynamic properties, and the clinical efficacy and safety of Entecavir in the treatment of nucleoside-naĩve and nucleoside-resistant HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). SEARCH METHODOLOGY: Computerized searches of PubMed and International Pharmaceutical Abstracts from 1985 to July 10, 2005, were performed with the search headings: Entecavir, BMS-200475, and chronic hepatitis B. Findings: Entecavir, a new deoxyguanosine analog, represents a third agent within the nucleoside/nucleotide HBV polymerase inhibitor class with distinct advantages over lamivudine and adefovir dipivoxil: it has a three-step mechanism of action, is the most potent inhibitor of HBV DNA polymerase, is not associated with any major adverse effects, and has a limited potential for resistance. In phase II and III clinical trials, Entecavir was found to be superior to lamivudine for all primary endpoints evaluated in both nucleoside-naïve and lamivudine-resistant patients. Entecavir was effective in both HBeAg-positive and HBeAg-negative nucleoside-naïve patients. At this time, optimal duration of Entecavir therapy is unknown. Conclusion: Entecavir represents a new first- or second-line treatment option for patients chronically infected with HBV. Long-term efficacy and safety studies as well as studies of Entecavir in combination with interferon products or other nucleoside/nucleotide analogs are eagerly awaited.
Entecavir for the treatment of chronic hepatitis B virus infection
Clin Ther 2006 Feb;28(2):184-203.PMID:16678641DOI:10.1016/j.clinthera.2006.02.012.
Objective: This article reviews the pharmacology/pharmacokinetics and therapeutic efficacy of Entecavir, which was approved on March 29, 2005, for the management of adult patients with chronic hepatitis B virus (HBV) infection who have active viral replication and/or elevations in liver transaminases or signs of active liver disease on histologic examination. Potential drug interactions and adverse events associated with the use of Entecavir are also reviewed. Methods: Relevant literature was identified through searches of MEDLINE (1996-July 2005) and BIOSIS (1993-July 2005). Search terms included, but were not limited to, Entecavir, BMS-200475, hepatitis B, pharmacology, pharmacokinetics, adverse events, and therapeutic use. Further publications were identified from the reference lists of the identified articles and through correspondence with the manufacturer of Entecavir. Results: Entecavir is highly selective for the HBV and inhibits all 3 steps of viral replication. Results of early studies indicated a 6% resistance potential after 48 weeks of therapy, although the potential may be higher in patients who harbor lamivudine-resistant mutants. The approved dosage in treatment-naive patients is 0.5 mg/d p.o., administered on an empty stomach; in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg/d p.o.. The oral tablet and solution can be used interchangeably. Entecavir is well absorbed orally, achieving a dose-related Cmax between 0.6 and 1.5 hours after administration. It is metabolized to a small extent and is not a substrate for the cytochrome P450 enzyme system. The mean elimination t(1/2) ranges from 77 to 149 hours in patients with normal kidney function. Entecavir is eliminated primarily in the urine via glomerular filtration and tubular secretion (62%-73%). No dose adjustment appears to be necessary in patients with moderate to severe liver disease alone. The potential for drug interactions with Entecavir appears to be minimal, although medications that inhibit tubular secretion of drugs (eg, probenecid) may be expected to prolong serum concentrations of Entecavir. One of the Phase III studies of Entecavir found statistically significant benefits compared with lamivudine in terms of improvements in liver histology after 48 weeks of therapy (72% vs 62%, respectively; P<0.009), the proportions of patients with undetectable HBV DNA titers on branched DNA signal amplification assay after 48 weeks of therapy (91% vs 65%; P<0.001), and the proportion with undetectable HBV DNA on polymerase chain reaction (PCR) assay after 48 weeks of therapy (69% vs 38%; P<0.001). In another Phase III study, patients who had failed to respond to lamivudine therapy responded to Entecavir: after 48 weeks of therapy, significant differences between Entecavir and lamivudine were seen in histologic improvement (55% vs 28%; P<0.001) and the proportion of patients with undetectable HBV DNA on PCR assay (21% vs 1%; P<0.001). Adverse events associated with Entecavir therapy were similar in character, severity, and incidence to those associated with placebo or lamivudine therapy. The most common adverse events in clinical trials of Entecavir were headache (17%-23% of patients), upper respiratory tract infection (18%-20%), cough (12%-15%), nasopharyngitis (9%-14%), fatigue (10%-13%), dizziness (9%), upper abdominal pain (9%-10%), and nausea (6%-8%). Conclusions: Entecavir is a new antiviral agent for the management of chronic HBV infection. Questions concerning the ideal length of therapy, long-term efficacy, and resistance rates over time await the results of ongoing clinical trials.
Potent efficacy of Entecavir (BMS-200475) in a duck model of hepatitis B virus replication
Antimicrob Agents Chemother 2002 Jan;46(1):82-8.PMID:11751115DOI:10.1128/AAC.46.1.82-88.2002.
The ability of Entecavir (ETV) to inhibit Duck hepatitis B virus (DHBV) infection in duck hepatocytes and ducklings was examined using lamivudine (3TC) as a comparator drug. ETV exhibited antiviral activity (50% effective concentration [EC(50)], 0.13 nM) in DHBV-infected duck hepatocytes that was >1,000-fold more potent than that of 3TC (EC(50), 138 nM). A 21-day treatment of ducklings with 1 mg of ETV per kg of body weight per day by oral gavage resulted in a mean reduction of log(10) 3.1 in serum DHBV DNA levels. Daily treatment with 0.1 mg of ETV/kg was nearly as effective, achieving an average viral DNA level decrease of log(10) 2.1. Reducing the daily dose of ETV to only 0.01 mg/kg resulted in an average viral DNA level decrease of log(10) 0.97. Daily treatment with 25 mg of 3TC/kg resulted in an average viral DNA level decrease of log(10) 0.66, compared to the log(10) 0.20 drop seen for ducklings given the vehicle alone. ETV was also more effective in decreasing the DHBV DNA levels in duck livers after 21 days of treatment, causing average drops of log(10) 1.41, log(10) 0.76, and log(10) 0.26 for dose levels of 1.0, 0.1, and 0.01 mg/kg, respectively, compared to a decrease of log(10) 0.06 for 3TC at a dose level of 25 mg/kg. Levels of viral covalently closed circular DNA in the treatment group receiving 1 mg of ETV/kg were reduced compared to those in the vehicle-treated group. ETV and 3TC were both well tolerated in all treated animals. These results show that ETV is a highly potent and effective antiviral in the DHBV duck model.
The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance
J Clin Invest 2001 Feb;107(4):449-55.PMID:11181644DOI:10.1172/JCI11100.
After receiving lamivudine for 3 years to treat chronic hepatitis B, 67-75% of patients develop B-domain L528M, C-domain M552I, or M552V mutations in the HBV polymerase that render hepatitis B virus (HBV) drug-resistant. The aim of this study was to evaluate the influence of these mutations on viral replication and resistance to antiviral agents. We investigated the replication fitness and susceptibility of the wild-type and five mutant HBVs (L528M, M552I, M552V, L528M/M552I, and L528M/M552V) to 11 compounds [lamivudine, adefovir, Entecavir (BMS-200475) (+)-BCH-189 (+/-)-FTC (racivir) (-)-FTC (emtricitabine) (+)-FTC, L-D4FC, L-FMAU (clevudine), D-DAPD, and (-)-carbovir] by transfecting HBV DNA into hepatoma cells and monitoring viral products by Southern blotting. The replication competency of the single C-domain mutants M552I and M552V was markedly decreased compared with that of wild-type HBV. However, addition of the B-domain mutation L528M restored replication competence. Only adefovir and Entecavir were effective against all five HBV mutants, and higher doses of these compounds were necessary to inhibit the double mutants compared with the single mutants. The B-domain mutation (L528M) of HBV polymerase not only restores the replication competence of C-domain mutants, but also increases resistance to nucleoside analogues.