Ebp 520;sch 503034

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: Ebp 520;sch 503034
• 英文别名: N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[2-(tert-butylcarbamoylamino)-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
• 化学式: C₂₇H₄₅N₅O₅
• 分子量: 519.7
• InChiKey: LHHCSNFAOIFYRV-UHFFFAOYSA-N

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

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

• 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）可能存在药代动力学相互作用，可能导致抗心律失常药物的浓度增加；存在严重和/或危及生命的不良反应风险。如果同时使用波塞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)

毒理性

• 相互作用

与华法林（改变华法林浓度）可能存在潜在的药物动力学相互作用。如果华法林与波塞普里韦同时使用，请密切监测国际标准化比率（INR）。

Potential pharmacokinetic interaction with warfarin (altered warfarin concentrations). Monitor international normalized ratio (INR) closely if warfarin is used concomitantly with boceprevir.

来源:Hazardous Substances Data Bank (HSDB)

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)

吸收、分配和排泄

博塞普韦口服给药后吸收，中位达峰时间（Tmax）为2小时。稳态下的药时曲线下面积（AUC）、Cmax（最大血药浓度）和Cmin（最小血药浓度）随着剂量的增加而增加，但增加幅度小于剂量比例，且在800毫克和1200毫克剂量下个体暴露度显著重叠，这表明在高剂量下吸收减少。累积作用很小（0.8到1.5倍），大约1天三次给药后达到药代动力学稳态。

Boceprevir was absorbed following oral administration with a median Tmax of 2 hours. Steady state AUC, Cmax, and Cmin increased in a less-than-dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1200 mg, suggesting diminished absorption at higher doses. Accumulation is minimal (0.8- to 1.5-fold) and pharmacokinetic steady state is achieved after approximately 1 day of three times daily dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

博塞普韦应在餐后服用。与空腹状态相比，食物可使博塞普韦的暴露量增加高达65%，在每日三次、每次800毫克的剂量下。无论餐饮类型（如高脂肪与低脂肪）或是在饭前5分钟、用餐中或饭后立即服用，博塞普韦的生物利用度相似。因此，博塞普韦的服用可以不考虑餐饮类型或餐饮的时间。

Boceprevir should be administered with food. Food enhanced the exposure of boceprevir by up to 65% at the 800 mg three times daily dose, relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, boceprevir may be taken without regard to either meal type or timing of the meal.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Boceprevir在健康受试者中的稳态表观分布容积（Vd/F）约为772升。

Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 L at steady state in healthy subjects.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• [EN] HCV PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES DE VHC
  申请人：TAIGEN BIOTECHNOLOGY CO LTD

  公开号：WO2011034518A1

  公开（公告）日：2011-03-24

  This invention relates to macrocyclic compounds shown in the specification. These compounds can be used to treat hepatitis C virus infection.

  这项发明涉及说明书中显示的大环化合物。这些化合物可用于治疗丙型肝炎病毒感染。
• HCV PROTEASE INHIBITORS
  申请人：Liu Chen-Fu

  公开号：US20110065737A1

  公开（公告）日：2011-03-17

  This invention relates to macrocyclic compounds of formula (I) shown in the specification. These compounds can be used to treat hepatitis C virus infection.

  本发明涉及规范中显示的式(I)的大环化合物。这些化合物可用于治疗丙型肝炎病毒感染。
• Peptides for the treatment of HCV infections
  申请人：Masse Craig

  公开号：US20090175824A1

  公开（公告）日：2009-07-09

  This invention relates to novel compounds that are peptides derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel peptides that are derivatives of boceprevir. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering an HCV NS3/NS4A protease inhibitor, such as boceprevir.

  本发明涉及新型化合物，它们是肽衍生物及其药学上可接受的盐。更具体地说，本发明涉及一种新型的肽衍生物，它是博西普韦的衍生物。本发明还提供了包含本发明中一种或多种化合物和载体的组合物，以及揭示的化合物和组合物在治疗通过给予HCV NS3/NS4A蛋白酶抑制剂（如博西普韦）有益治疗的疾病和病症的方法中的用途。
• PROCESS AND INTERMEDIATES FOR THE PREPARATION OF 3-(AMINO)-3-CYCLOBUTYLMETHYL-2-HYDROXY-PROPIONAMIDE OR SALTS THEREOF
  申请人：Chen Minzhang

  公开号：US20090312576A1

  公开（公告）日：2009-12-17

  In one embodiment, the present application relates to a process of making a compound of formula I: and to certain intermediate compounds that are made within the process of making the compound of formula I.

  在一种实施方式中，本申请涉及制备化合物I的过程，以及在制备化合物I的过程中制备的某些中间化合物。
• PREPARATION OF 3-AMINO-3-(CYCLOBUTYLMETHYL)-2-(HYDROXY)-PROPIONAMIDE HYDROCHLORIDE
  申请人：Park Jeonghan

  公开号：US20100113821A1

  公开（公告）日：2010-05-06

  Disclosed is a process for preparing 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide hydrochloride, an intermediate useful in the preparation of the HCV protease inhibitor (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.

  本发明公开了一种制备3-(氨基)-3-环丁基甲基-2-羟基-丙酰胺盐酸盐的方法，该中间体在制备HCV蛋白酶抑制剂(1R,5S)-N-[3-氨基-1-(环丁基甲基)-2,3-二氧代丙基]-3-[2(S)-[[[(1,1-二甲基乙基)氨基]羰基]氨基]-3,3-二甲基-1-氧代丁基]-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2(S)-羧酰胺中有用。