特拉匹韦 | 402957-28-2

• 物质功能分类: 生物化工 - 抑制剂 - 蛋白酶体(Proteases)
• 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: 特拉匹韦
• 中文别名: 特拉匹韦（VX-950）；特拉匹伟；VX-950
• 英文名称: (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
• 英文别名: Telaprevir；(1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide；(1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-[(2-pyrazinylcarbonyl)amino] acetyl]amino]-3,3-dimethylbutanoyl]-N-[(1S)-1-[(cyclopropylamino)(oxo)acetyl]butyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide；(1S,3aR,6aS)-2-((2S)-2-{[(2S)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino}-3,3-dimethylbutanoyl)-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide；(1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide；(3S,3aS,6aR)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide
• CAS: 402957-28-2
• 化学式: C₃₆H₅₃N₇O₆
• 分子量: 679.86
• InChiKey: BBAWEDCPNXPBQM-GDEBMMAJSA-N

物化性质

• 熔点：
  116-123°C
• 密度：
  1.25
• 溶解度：
  可溶于氯仿、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  White to off-white powder
• 蒸汽压力：
  9.93X10-26 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  49
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  180
• 氢给体数：
  4
• 氢受体数：
  8

ADMET

代谢

特拉普韦通过水解、氧化和还原被广泛代谢。特拉普韦的主要代谢物包括吡嗪酸，这是一种在α-酮酰胺键发生还原的代谢物，以及特拉普韦的R-对映异构体，其活性比母体化合物低30倍，被发现是主要的代谢物。参与特拉普韦代谢的主要酶是CYP3A4。一些代谢作用由醛酮还原酶和其他还原酶执行。

Telaprevir is extensively metabolized via hydrolysis, oxidation, and reduction. The major metabolites of Telaprevir are pyrazinoic acid, a metabolite that underwent reduction at the α-ketoamide bond, and the R-diastereomer of telaprevir which is 30-fold less active than the parent compound were found to be the predominant metabolites. The primary enzyme involved in the metabolism of Telaprevir is CYP3A4. Some metabolism is performed by aldo-keto reductases and other reductases.

来源:DrugBank

代谢

特拉匹韦在肝脏中被广泛代谢，涉及水解、氧化和还原。在粪便、血浆和尿液中检测到多种代谢物。在反复口服给药后，特拉匹韦的R-对映体（活性降低30倍）、吡嗪酸和一种在特拉匹韦的α-酮酰胺键发生还原的代谢物（无活性）被确定为特拉匹韦的主要代谢物。

Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the alpha-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模随机对照试验中，使用特拉普雷韦、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，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。然而，特拉普雷韦与高皮疹发生率相关，有时与超敏反应的特征相关，包括罕见的药物反应伴嗜酸性粒细胞增多和史蒂文斯-约翰逊综合征。这些严重的皮肤反应通常伴有肝损伤的实验室证据（ALT和碱性磷酸酶升高）。在报告的病例中，然而，皮疹和其他超敏反应的特征通常掩盖了肝损伤，没有报告与黄疸相关。 特拉普雷韦治疗的另一种罕见但严重的肝脏并发症发生在有晚期纤维化或肝硬化的患者中，其中一部分治疗对象出现了新的、看似自发的肝脏失代偿。在有晚期纤维化或肝硬化以及之前有失代偿病史的患者中，失代偿尤其常见。失代偿的原因尚不清楚，特拉普雷韦相对于聚乙二醇干扰素和利巴韦林的作用无法确定。尽管如此，在慢性丙型肝炎肝硬化三联疗法的上市后研究中，报告有2%至8%的患者出现失代偿，1%至3%的患者因肝衰竭死亡。 特拉普雷韦、聚乙二醇干扰素和利巴韦林组合的可能性评分：B（可能是肝硬化或晚期纤维化患者肝损伤和肝脏失代偿的原因）。

In large randomized controlled trials, triple therapy with telaprevir, 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. Telaprevir, however, was associated with a high rate of rash, which was sometimes associated with features of hypersensitivity, including rare instances of DRESS and Stevens Johnson syndrome. These severe cutaneous reactions are often accompanied by laboratory evidence of hepatic injury (ALT and alkaline phosphatase elevations). In reported cases, however, the rash and other features of hypersensitivity typically overshadowed the hepatic injury and none were reported to be associated with jaundice. Another rare but severe hepatic complications of telaprevir therapy occurs in patients with advanced fibrosis or cirrhosis, among whom de novo, seemingly spontaneous hepatic decompensation occurred in a proportion of treated subjects. Decompensation was particularly common in patients with advanced fibrosis or cirrhosis with a previous history of decompensation. The cause of the decompensation was not clear and the separate role of telaprevir in contrast to peginterferon and ribavirin could not be defined. Nevertheless, in postmarketing studies of triple therapy of chronic hepatitis C with cirrhosis, decompensation was reported in 2% to 8% of patients, and deaths from hepatic failure in 1% to 3%. Likelihood score for the combination of telaprevir, peginterferon and ribavirin: B (likely cause of liver injury and hepatic decompensation in patients with preexisting cirrhosis or advanced fibrosis).

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

乳哺期间使用概要：Telaprevir 在美国已不再销售，且未在哺乳期母亲中进行研究。由于必须与利巴韦林和聚乙二醇干扰素α联合使用，因此在哺乳期间不是一个好的选择。当其上市时，制造商建议服用 Telaprevir 的母亲不要给她们的婴儿哺乳。 ◉ 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。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Telaprevir is no longer marketed in the United States and has not been studied in nursing mothers. Because it must be used with ribavirin and peginterferon alfa, it is not considered a good choice during breastfeeding. When it was marketed, the manufacturer recommended that mothers taking telaprevir not breastfeed their infants. ◉ 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

泰拉普雷韦尔是CYP3A的强抑制剂。当泰拉普雷韦尔与那些高度依赖CYP3A清除且血药浓度升高与严重和/或危及生命的事件（治疗指数狭窄）相关的药物联合使用时，是禁忌的。泰拉普雷韦尔与强烈诱导CYP3A的药物联合使用时也是禁忌的，因为这可能导致泰拉普雷韦尔的暴露量降低和疗效丧失。

Telaprevir is a strong inhibitor of CYP3A. Telaprevir is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Telaprevir is contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与P-糖蛋白诱导剂或抑制剂药物的潜在药代动力学相互作用，可能会改变替拉瑞韦的浓度。

Potential pharmacokinetic interaction with drugs that are inducers or inhibitors of P-glycoprotein, with possible alteration in telaprevir concentrations.

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或心脏心律不齐，所以禁忌同时使用telaprevir和alfuzosin。

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

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

特拉普雷韦在给药后4-5小时达到血浆峰浓度。绝对生物利用度尚未确定。与正常脂肪餐（21克脂肪）一起服用时，与禁食状态相比，暴露量增加235%。在低脂肪（3.6克脂肪）和高脂肪（56克脂肪）餐后，暴露量分别增加了117%和330%。

Telaprevir reaches peak plasma concentration 4-5hours after administration. Absolute bioavailability has not been determined. When taken with a normal fat meal (21g of fat), exposure increases by 235% compared to fasting conditions. With low (3.6g of fat) and high fat (56g of fat) meals, exposure increased 117% and 330% respectively.

来源:DrugBank

吸收、分配和排泄

• 消除途径

泰拉普雷韦尔主要通过粪便排出（82%），少量通过呼吸排出（9%），通过尿液排出的非常少（1%）。粪便中药物以母体化合物形式存在的比例为31.9%，以母体化合物的R-对映异构体形式存在的比例为18.8%。

Telaprevir is mainly eliminated in the feces (82%) with a smaller amount eliminated via expiration (9%) and very little in the urine (1%). 31.9% and 18.8% of drug in the feces was present as the parent compound and R-diastereomer of the parent compound respectively.

来源:DrugBank

吸收、分配和排泄

• 分布容积

泰拉帕韦的估计表观分布容积为252升，个体间变异性为72%。

The estimated apparent volume of distribution for Telapravir is 252 litres with an inter-individual variability of 72%.

来源:DrugBank

吸收、分配和排泄

• 清除

特拉普雷韦的人体总清除率估计为每小时32.4升，个体间变异性为27.2%。

Telaprevir has an estimated aparent total body clearance of 32.4 liters per hour with an interindividual variability of 27.2%.

来源:DrugBank

吸收、分配和排泄

泰拉普雷韦的药代动力学特性已经在健康成年受试者和慢性丙型肝炎受试者中进行了评估。在未经治疗的1型慢性丙型肝炎患者中，联合使用泰拉普雷韦（每8小时750毫克）、聚乙二醇干扰素α和利巴韦林多次给药后，平均（标准差）Cmax为3510（1280）ng/mL，Cmin为2030（930）ng/mL，AUC8h为22,300（8650）ng·h/mL。

The pharmacokinetic properties of telaprevir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following multiple doses of telaprevir (750 mg every 8 hr) in combination with peginterferon alfa and ribavirin in treatment-naive subjects with genotype 1 chronic hepatitis C, mean (SD) Cmax was 3510 (1280) ng/mL, Cmin was 2030 (930) ng/mL, and AUC8h was 22,300 (8650) ng.hr/mL.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• 海关编码：
  29339900
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  | 2~8°C |

制备方法与用途

应用 特拉匹韦是一种有效的选择性可逆HCV NS3-4A蛋白酶抑制剂，作用于基因1型（H株） 蛋白酶结构域和NS4A辅因子肽。

生物活性 Telaprevir (VX-950, LY-570310, MP-424) 是一种丙型肝炎病毒(HCV) -4A丝氨酸蛋白酶抑制剂，其IC50值为0.354 μM。

靶点

Target	Value
HCV -4A SErine proteaSE	0.35 μM

体外研究 Telaprevir 作用于Con1(基因型1b)亚基因组HCV复制细胞，抑制丙型肝炎病毒 -4A丝氨酸蛋白酶活性，导致病毒多聚蛋白加工受抑制，并随后使病毒RNA和蛋白质水平降低。这种作用存在时间和剂量依赖性。具体IC50值分别为：温育24小时、48小时、72小时和120小时时，IC50值分别为0.574 μM, 0.488 μM, 0.210 μM和0.139 μM。Telaprevir 处理HCV复制细胞（包括亲本Huh-7和HepG2细胞）48小时后，对细胞无毒性，并且在17.5 μM剂量下能够完全消除复制细胞中的HCV RNA，在撤销处理13天后未见反弹。Telaprevir与IFN-α联用时，适度提高了协同作用，降低了HCV RNA复制并抑制了耐药突变，但没有明显毒性。

体内研究 在小鼠模型中，以10 mg/kg和25 mg/kg剂量口服Telaprevir 可降低依赖于HCV蛋白酶的裂解，并减少SEAP从肝脏分泌到血液中的量，分别降低了18.7%和18.4%。以200 mg/kg剂量处理基因型1b HCV感染的人肝细胞的小鼠1周后，可观察到HCV RNA水平降低；与MK-0608 (50 mg/kg) 联用处理小鼠持续4周，则可完全去除体内的病毒。

用途 用于治疗丙型肝炎的新药

反应信息

• 作为反应物：
  描述：

  特拉匹韦 生成
  参考文献：
  名称：

  Deuterated hepatitis C protease inhibitors

  摘要：

  一种氘代的α-酮氨基立体特异化合物，其化学式为其中D表示立体特异碳原子上的一个氘原子。

  公开号：

  US20070225297A1
• 作为产物：
  描述：

  [2H]-Telaprevir 生成 特拉匹韦
  参考文献：
  名称：

  Deuterated hepatitis C protease inhibitors

  摘要：

  一种氘代的α-酮氨基立体特异化合物，其化学式为其中D表示立体特异碳原子上的一个氘原子。

  公开号：

  US20070225297A1
• 作为试剂：
  描述：

  (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((2R,3S)-1-(cyclopropylamino)-2-hydroxy-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide 、 溴化钠 、 碳酸氢钠 、 2,2,6,6-四甲基哌啶氧化物 、 sodium hypochlorite 在 Disodium;sulfite 、 magnesium sulfate 、 ethyl acetate dichloromethane 、 特拉匹韦 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 1.67h， 生成 特拉匹韦
  参考文献：
  名称：

  PROCESSES AND INTERMEDIATES

  摘要：

  本发明涉及化合物和制备蛋白酶抑制剂的方法，特别是丝氨酸蛋白酶抑制剂。这些蛋白酶抑制剂对治疗HCV感染有用。

  公开号：

  US20130172276A1

文献信息

• HCV PROTEASE INHIBITORS AND USES THEREOF
  申请人：Niu Deqiang

  公开号：US20090176858A1

  公开（公告）日：2009-07-09

  The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

  本发明提供了化合物、药学上可接受的组合物以及使用它们的方法。
• 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。
• Pharmaceutical formulations and methods of treatment using the same
  申请人：Malcolm A. Bruce

  公开号：US20070010431A1

  公开（公告）日：2007-01-11

  Pharmaceutical formulations containing at least one compound of Formulae I-XXVI herein and at least one surfactant. Pharmaceutically acceptable carriers and excipients may also be included in the formulations. The formulations of the present invention are suited for use in single unit dosages.

  含有本文中的至少一种I-XXVI式化合物和至少一种表面活性剂的制药配方。 制剂中还可以包括药用可接受的载体和辅料。 本发明的制剂适用于单剂量使用。
• [EN] PROCESS FOR THE PREPARATION OF TELAPREVIR AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉ POUR LA PRÉPARATION DE TÉLAPRÉVIR ET D'INTERMÉDIAIRES DE TÉLAPRÉVIR
  申请人：RANBAXY LAB LTD

  公开号：WO2014203208A1

  公开（公告）日：2014-12-24

  The present invention provides a process for the preparation of telaprevir and intermediates thereof.

  本发明提供了一种用于制备特拉普韦和其中间体的过程。
• [EN] PROCESS FOR THE PREPARATION OF TELAPREVIR AND ITS INTERMEDIATES<br/>[FR] PROCÉDÉ POUR LA PRÉPARATION DE TÉLAPRÉVIR ET D'INTERMÉDIAIRES DE TÉLAPRÉVIR
  申请人：RANBAXY LAB LTD

  公开号：WO2014203224A1

  公开（公告）日：2014-12-24

  The present invention provides a process for the preparation of telaprevir and its intermediates.

  本发明提供了一种用于制备特拉普韦和其中间体的方法。