博赛泼维 | 394730-60-0

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗病毒类药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 中文名称: 博赛泼维
• 中文别名: 波普瑞韦；(1R,2S,5S)-N-(4-氨基-1-环丁基-3,4-二氧代丁烷-2-基)-3-[(2S)-2-(叔丁基氨基甲酰氨基)-3,3-二甲基丁酰基]-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺；博塞匹韦；波西普韦；博赛匹韦；博赛匹维
• 英文名称: boceprevir
• 英文别名: Victrelis；(1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-(2S)-carboxamide；(1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide；(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicylo[3.1.0]hexane-2-carboxamide；(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide；(1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S)-2-(tert-butylcarbamoylamino)-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
• CAS: 394730-60-0
• 化学式: C₂₇H₄₅N₅O₅
• 分子量: 519.685
• InChiKey: LHHCSNFAOIFYRV-DOVBMPENSA-N

物化性质

• 熔点：
  >107°C (dec.)
• 密度：
  1.162
• 溶解度：
  可溶于 DMSO（升温时高达 15 mg/ml）
• 颜色/状态：
  White to off-white amorphous powder

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  151
• 氢给体数：
  4
• 氢受体数：
  5

ADMET

代谢

博塞普雷韦主要经过醛酮还原酶介导的途径代谢，产生一对对映异构体混合物，其暴露程度比原化合物高4倍。博塞普雷韦还通过CYP3A4/5进行氧化代谢，但程度较小。

Bocepravir is primarily metabolized via the aldo-ketoreductase-mediated pathway producing a diastereomeric mix of metabolites at a 4 fold greater exposure than the parent compound. Boceprevir also undergoes oxidative metabolism via CYP3A4/5, although to a lesser extent.

来源:DrugBank

代谢

体外研究表明，波塞普里韦主要通过aldo-酮还原酶（AKR）介导的途径代谢为对HCV无效的酮还原代谢物。在单次口服800毫克(14)C-波塞普里韦后，循环中最丰富的代谢物是一对酮还原代谢物的对映异构体混合物，其平均暴露量大约是波塞普里韦的4倍。波塞普里韦还以较小程度地通过CYP3A4/5介导的氧化代谢。

Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-ketoreductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800-mg oral dose of (14)C-boceprevir, the most abundant circulating metabolites were a diasteriomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4-fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模随机对照试验中，使用波塞普里韦、聚乙二醇干扰素和利巴韦林的三联疗法与高不良事件发生率相关，这些不良事件通常需要调整剂量，并导致5%至20%的患者提前终止治疗。然而，血清ALT升高和临床上明显的肝脏损伤通常并未被提及作为治疗的不良事件。这种情况的例外发生在有预先存在肝硬化的患者中，其中一部分接受治疗的患者出现了新的、看似自发的肝脏失代偿。失代偿的原因尚不清楚，波塞普里韦与聚乙二醇干扰素和利巴韦林以及即使没有治疗也可能发生的情况的单独作用难以界定。尽管如此，在针对慢性丙型肝炎肝硬化的三联疗法的上市后研究中，报告有3%至8%的患者出现失代偿，因肝衰竭死亡的病例占1%至3%。

In large randomized controlled trials, triple therapy with boceprevir, peginterferon and ribavirin was associated with a high rate of adverse events that often required dose adjustments and led to early discontinuation in 5% to 20% of patients. However, serum ALT elevations and clinically apparent liver injury were not generally mentioned as adverse events of therapy. The exception to this occurred in patients with preexisting cirrhosis in whom de novo, seemingly spontaneous hepatic decompensation occurred in a proportion of treated subjects. The cause of the decompensation was not clear and the separate role of boceprevir from peginterferon and ribavirin and from what might happen even without therapy could not be easily defined. Nevertheless, in postmarketing studies of triple therapy of chronic hepatitis C with cirrhosis, decompensation was reported in 3% to 8% of patients and deaths from hepatic failure in 1% to 3%.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：Boceprevir 已从美国市场撤出。它尚未在正在接受丙型肝炎治疗的哺乳期母亲中进行研究。因为它必须与利巴韦林和聚乙二醇干扰素 alfa 一起使用，所以在哺乳期间被认为不是一个好选择。在更多数据出现之前，可能更倾向于选择另一种药物，特别是在哺乳新生儿或早产儿时。 丙型肝炎不会通过母乳传播，并且已经证明母乳可以灭活丙型肝炎病毒 (HCV)。然而，疾病控制中心建议，如果患有 HCV 感染的母亲乳头裂开或出血，应考虑停止哺乳。目前尚不清楚这一警告是否适用于正在接受丙型肝炎治疗的母亲。 出生在 HCV 感染母亲的婴儿应进行 HCV 感染检测；因为母体抗体在生命的前 18 个月内存在，并且在婴儿产生免疫反应之前，推荐进行核酸检测。 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 对哺乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Boceprevir has been removed from the US market. It has not been studied in nursing mothers being treated for hepatitis C infection. Because it must be used with ribavirin and peginterferon alfa, it is not considered a good choice during breastfeeding. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Hepatitis C is not transmitted through breastmilk and breastmilk has been shown to inactivate hepatitis C virus (HCV). However, the Centers for Disease Control recommends that mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. It is not clear if this warning would apply to mothers who are being treated for hepatitis C. Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

与博塞普韦同时使用可能大幅降低博塞普韦血药浓度和疗效的强效CYP3A4/5诱导剂（例如，卡马西平、苯巴比妥、苯妥英、利福平、圣约翰草[贯叶连翘]）是禁忌的。

Concomitant use of boceprevir and potent CYP3A4/5 inducers that may substantially reduce plasma boceprevir concentrations and efficacy (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort [Hypericum perforatum]) is contraindicated.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与alfuzosin（增加alfuzosin浓度）可能存在药代动力学相互作用。因为增加的alfuzosin浓度可能导致低血压，所以禁忌同时使用boceprevir和alfuzosin。

Potential pharmacokinetic interaction with alfuzosin (increased alfuzosin concentrations). Concomitant use of boceprevir and alfuzosin is contraindicated because increased alfuzosin concentrations may result in hypotension.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与抗心律失常药物（胺碘酮、苄普地尔（在美国已不再商业销售）、氟卡尼、普罗帕酮、奎尼丁）可能存在潜在的药代动力学相互作用，可能导致抗心律失常药物浓度增加；可能会出现严重和/或危及生命的不良反应。如果同时使用波塞普韦和抗心律失常药物，应谨慎使用并监测抗心律失常药物的血药浓度。

Potential pharmacokinetic interaction with antiarrhythmic agents (amiodarone, bepridil (no longer commercially available in US), flecainide, propafenone, quinidine) may result in increased concentrations of the antiarrhythmic agent; potential for serious and/or life-threatening adverse effects. If boceprevir and antiarrhythmic agents are used concomitantly, use caution and monitor plasma concentrations of the antiarrhythmic agent.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

Boceprevir在给药后2小时达到血浆峰浓度。绝对生物利用度尚未确定。与食物同服时，暴露量可增加达65%。在胶囊中，Boceprevir由两种对映异构体以1:1的比例组成。在血浆中，这一比例变为2:1，有利于活性对映异构体。

Boceprevir reaches peak plasma concentration 2 hours after administration. Absolute bioavailability has not been determined. When taken with food exposure increases up to 65%. In capsule, Boceprevir consists of two diaseromers in a 1:1 ratio. In plasma this ratio changes to 2:1 favoring the active diastereomer.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Boceprevir 主要通过粪便排出（79%），少量通过尿液排出（9%）。大约 8% 和 3% 分别以原形药物在粪便和尿液中排出。

Boceprevir is mainly eliminated in the feces (79%) with a small amount eliminated in the urine (9%). Approximately 8% and 3% is excreted as the parent compound in the feces and urine respectively.

来源:DrugBank

吸收、分配和排泄

• 分布容积

博塞普拉韦的平均表观分布体积在稳态时为772升。

The mean apparent volume of distribution for Bocepravir is 772 litres at steady state.

来源:DrugBank

吸收、分配和排泄

• 清除

Boceprevir的平均总身体清除率为每小时161升。

Boceprevir has a mean total body clearance of 161 liters per hour.

来源:DrugBank

吸收、分配和排泄

在单独接受每日三次800毫克博塞普韦的健康受试者中，博塞普韦的药物暴露以AUC(T)5408 ng·小时/毫升（n=71）、Cmax 1723 ng/毫升（n=71）和Cmin 88 ng/毫升（n=71）为特征。健康受试者与HCV感染受试者的药代动力学结果相似。

In healthy subjects who received 800 mg three times daily alone, boceprevir drug exposure was characterized by AUC(T) of 5408 ng. hr per mL (n=71), Cmax of 1723 ng per mL (n=71), and Cmin of 88 ng per mL (n=71). Pharmacokinetic results were similar between healthy subjects and HCV-infected subjects.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  -20℃

制备方法与用途

药代动力学

波普瑞韦主要通过肝脏排泄。在肝功能异常患者中，药物的血浆峰浓度和药时曲线下面积均有上升，但药物消除半衰期与健康人无差异。在肾功能不全终末期患者中，波普瑞韦的各项药物代谢动力学指标与健康人无明显差异，并且本品不能经血液透析清除。因此，肝肾功能不全患者使用波普瑞韦时无需减量。

用途

波普瑞韦是一种口服的丙型肝炎病毒非结构蛋白3/4A丝氨酸蛋白酶抑制剂，直接作用于病毒酶的功能区，即病毒蛋白酶。通过与NS3/4A ASP结合，抑制病毒复制。波普瑞韦是针对丙型肝炎病毒NS3丝氨酸蛋白酶的一种抑制剂，用于治疗丙型肝炎病毒感染。它也是一种新型冠状病毒相关研究产品。

适应症

波普瑞韦不可单独使用，适用于与聚乙二醇干扰素α和利巴韦林联用，以治疗基因型1感染的慢性丙型肝炎CHC，在有代偿性肝病（≥18岁）成年患者中，包括肝硬化、既往未接受过治疗或曾经对干扰素和利巴韦林治疗无效的患者。

生物活性

波普瑞韦（Boceprevir, EBP 520, SCH 503034）是一种口服的直接作用于丙型肝炎病毒（HCV）蛋白酶的抑制剂，对NS3蛋白酶的Ki值为14 nM。在治疗慢性丙型肝炎C（基因型1）时，常与其他抗病毒药物联合给药。

靶点

Target	Value
NS3/4A protease	14 nM (Ki)

反应信息

• 作为反应物：
  描述：

  博赛泼维 生成 (1R,2S,5S)-N[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-di-oxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide 、 boceprevir
  参考文献：
  名称：

  Administration of HCV protease inhibitors in combination with food to improve bioavailability

  摘要：

  提供了一种治疗、预防或改善乙型肝炎患者一种或多种症状的方法，包括在给予患者至少一种HCV蛋白酶抑制剂的步骤中与食物结合。还提供了一种增加HCV蛋白酶抑制剂生物利用度的方法和增加患者血清中HCV蛋白酶抑制剂水平的方法。所有方法包括在与食物结合的情况下给予患者至少一种HCV蛋白酶抑制剂，所述至少一种HCV蛋白酶抑制剂选自本文所述的化合物I-XXVI的组。与不与食物一起给药相比，本发明化合物与食物结合给药提供了改善的生物利用度和增加的化合物峰值血清水平。

  公开号：

  US20060281688A1
• 作为产物：
  描述：

  1-氰基-3-环丁基-1-羟基丙烷-2-氨基甲酸叔丁酯 在 N-甲基吗啉 N-甲基吗啉 、 盐酸 、 二氯乙酸 、 lithium hydroxide 、 氯化铵 、 二甲基亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 3-羟基-1,2,3-苯并三嗪-4(3H)-酮 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 152.0h， 生成 博赛泼维
  参考文献：
  名称：

  Discovery of (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor:  A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection

  摘要：

  Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

  DOI：

  10.1021/jm060325b

文献信息

• Methods of treating hepatitis C virus
  申请人：Gupta K. Samir

  公开号：US20060276406A1

  公开（公告）日：2006-12-07

  Methods for preventing, ameliorating or treating one or more symptoms of Hepatitis C virus (HCV), modulating HCV protease activity and/or inhibiting cathepsin activity in a subject, wherein the methods comprise administering to a subject in need of such treatment a dosage formulation containing at least one compound of Formulae I-XXVI herein, wherein the dosage formulation is capable of maintaining an average Cmin plasma concentration of the compound at or above 10 ng/ml.

  预防、改善或治疗丙型肝炎病毒（HCV）的一个或多个症状的方法，调节受试者中的HCV蛋白酶活性和/或抑制半胱氨酸蛋白酶活性，其中所述方法包括向需要此类治疗的受试者施用含有本文中的至少一种I-XXVI式化合物的剂量配方，其中剂量配方能够维持化合物的平均Cmin血浆浓度在或高于10 ng/ml。
• (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as inhibitor of hepatitis C virus NS3/NS4a serine protease
  申请人：Njoroge George F.

  公开号：US20050249702A1

  公开（公告）日：2005-11-10

  The present invention discloses the compound of Formula 3 as an inhibitor of HCV protease, as well as methods for preparing the compound. In another embodiment, the invention discloses pharmaceutical compositions comprising the compound as well as methods of using them to treat disorders associated with the HCV protease.

  本发明公开了化合物Formula 3作为HCV蛋白酶抑制剂，以及制备该化合物的方法。在另一实施例中，本发明公开了包含该化合物的药物组合物，以及使用它们治疗与HCV蛋白酶相关的疾病的方法。
• Methods for treating hepatitis C
  申请人：Albrecht K. Janice

  公开号：US20060276405A1

  公开（公告）日：2006-12-07

  Methods of treating hepatitis C are provided comprising using a therapeutically effective amount of at least one novel hepatitis C (“HCV”) protease inhibitor or, alternatively, at least one antiviral or immuno-modulating HCV agent, which is not an HCV protease inhibitor, for a first treatment period. Subsequently, a combination of the at least one novel hepatitis C (“HCV”) protease inhibitor and the at least one antiviral or immuno-modulating HCV agent are administered in a therapeutically effective amount for a second treatment period. The methods are provided for treating a wide variety of diseases, disorders and symptoms associated with hepatitis C virus by modulating the activity of HCV protease (for example HCV NS3/NS4a serine protease) in a subject.

  提供了治疗丙型肝炎的方法，包括使用至少一种新型丙型肝炎（“HCV”）蛋白酶抑制剂的治疗有效量，或者选择至少一种不是HCV蛋白酶抑制剂的抗病毒或免疫调节HCV药物，用于第一治疗期。随后，在第二治疗期内以治疗有效量给予至少一种新型丙型肝炎（“HCV”）蛋白酶抑制剂和至少一种抗病毒或免疫调节HCV药物的组合。这些方法用于通过调节受试者中HCV蛋白酶（例如HCV NS3/NS4a丝氨酸蛋白酶）的活性来治疗与丙型肝炎病毒相关的各种疾病、疾病和症状。
• Medicaments and methods combining a HCV protease inhibitor and an AKR competitor
  申请人：Ghosal Anima

  公开号：US20060276404A1

  公开（公告）日：2006-12-07

  Disclosed are medicaments, pharmaceutical compositions, pharmaceutical kits, and methods based on combinations of a hepatitis C virus (HCV) protease inhibitor and an aldo-keto reductase (AKR) competitor, for concurrent or consecutive administration in treating, preventing, or ameliorating one or more symptoms of HCV, treating disorders associated with HCV, or inhibiting cathepsin activity in a subject.

  揭示了基于丙型肝炎病毒（HCV）蛋白酶抑制剂和醛酮还原酶（AKR）竞争剂的组合的药物、药物组合物、药物套装和方法，用于同时或连续给药以治疗、预防或缓解HCV的一个或多个症状，治疗与HCV相关的疾病，或抑制受试者体内的半胱氨酸蛋白酶活性。
• Liver/plasma concentration ratio for dosing hepatitis C virus protease inhibitor
  申请人：White E. Ronald

  公开号：US20070021351A1

  公开（公告）日：2007-01-25

  Compositions and therapeutic combinations are provided including at least one compound selected from the group consisting of compounds of Formulae I to XXVI as defined herein as well as methods of treatment, prevention or amelioration of one or more symptoms of hepatitis C, treating disorders associated with HCV virus, modulating activity of HCV protease, in which liver to plasma concentration ratio of the compound ranges from about 2:1 to about 10:1.

  提供了包括至少一种从本文中定义的I到XXVI式化合物组中选择的化合物的组合物和治疗组合，以及治疗、预防或改善丙型肝炎的一个或多个症状的方法，治疗与HCV病毒相关的疾病，调节HCV蛋白酶活性，其中化合物的肝脏到血浆浓度比范围约为2:1至约为10:1。