帕利普韦 | 1216941-48-8

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 帕利普韦
• 中文别名: 维卢瑞韦
• 英文名称: paritaprevir
• 英文别名: (2R,6S,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide；(2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a (5H)-carboxamide；ABT-450；(2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methyl-2-pyrazinyl)carbonyl]amino}-5,16-dioxo-2-(6-phenanthridinyloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide；(1S,4R,6S,7Z,14S,18R)-N-cyclopropylsulfonyl-14-[(5-methylpyrazine-2-carbonyl)amino]-2,15-dioxo-18-phenanthridin-6-yloxy-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxamide
• CAS: 1216941-48-8
• 化学式: C₄₀H₄₃N₇O₇S
• 分子量: 765.89
• InChiKey: UAUIUKWPKRJZJV-QPLHLKROSA-N

物化性质

• 密度：
  1.45±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO:30.0(最大浓度 mg/mL);39.2(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  55
• 可旋转键数：
  7
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  198
• 氢给体数：
  3
• 氢受体数：
  10

ADMET

代谢

Paritaprevir 主要通过 CYP3A4 代谢，其次通过 CYP3A5 代谢 [FDA 标签]。

Paritaprevir is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5 [FDA Label].

来源:DrugBank

毒理性

• 肝毒性

在大规模随机对照试验中，使用Viekira Pak治疗的患者的血清转氨酶升高超过正常上限（ULN）5倍的发生率为1%至2%，这一比率低于安慰剂治疗（3%至7%）的发生率。这些升高通常是无需调整剂量就能自行缓解的无症状且短暂的，大约有1%的患者需要停药。尽管在治疗期间血清酶升高很常见，但在上市前的研究中很少报告有临床明显的肝损伤。然而，自从Viekira Pak在美国广泛使用以及在其它地方多年的临床使用中，偶尔会有报告显示明显的血清转氨酶升高伴随症状和轻度黄疸，尽管这些情况在已发表的文献中没有描述。此外，一些患有慢性丙型肝炎和晚期肝硬化的患者在D-O-P/r治疗期间突然出现肝功能失代偿。接受其他口服抗病毒组合治疗的患者，如索非布韦与达卡他韦、雷迪帕韦或西美瑞韦治疗的患者，也有类似的病例报告。因此，这种现象可能与特定药物无关，而是对所有强效丙型肝炎抗病毒治疗的常见反应，可能是对HCV突然清除的悖论性反应。或者，这些病例可能是自发的、巧合的，与抗病毒治疗无关。这些治疗在肝硬化患者中的试验没有安慰剂对照，因此无法很好地定义因丙型肝炎肝硬化患者的自发肝功能失代偿率。无论原因如何，高达10%的肝硬化患者在强效抗病毒治疗期间出现失代偿，这使得前瞻性监测是可取的，如果出现肝衰竭的证据，应立即停止治疗。 因此，Viekira Pak方案中包含的五种抗病毒化合物（达沙布韦、奥比他韦、帕立他韦、利托那韦和利巴韦林）在治疗期间与突然的ALT升高有关，但罕见于临床明显的肝损伤。在已有肝硬化的患者中，使用Viekira Pak进行抗病毒治疗与乳酸酸中毒和肝功能失代偿的发作有关。这些突然、严重的不良事件的原因不明，但它们通常是严重且威胁生命的，需要立即停止治疗，进行重症监护管理，并考虑紧急肝移植。 可能性评分：C（可能导致已有肝硬化的患者发生肝损伤的原因）。

In large randomized controlled trials, serum aminotransferase elevations more than 5 times the upper limit of normal (ULN) occurred in 1% to 2% of Viekira Pak treated patients. Interestingly, this rate was lower than occurred with placebo therapy (3% to 7%). The elevations were generally asymptomatic and short lived, resolving with or without dose modification and requiring drug discontinuation in approximately 1% of patients. Despite the frequency of serum enzyme elevations during therapy, clinically apparent liver injury was rarely reported in preregistration studies. However, since the general availability of Viekira Pak in the United States and during years of clinical use elsewhere, occasional instances of marked serum aminotransferase elevations with symptoms and mild jaundice have been reported, although not described in the published literature. Furthermore, some patients with chronic hepatitis C and advanced cirrhosis have developed sudden hepatic decompensation during therapy with D-O-P/r. Similar episodes have been described in patients receiving other oral antiviral combinations such as sofosbuvir with daclatasvir, ledipasvir or simeprevir. Thus, this phenomenon may be unrelated to a specific agent, but rather common to all potent antiviral therapies for hepatitis C and perhaps is a paradoxical response to sudden clearance of HCV. Alternatively, these episodes may be spontaneous, coincidental and unrelated to the antiviral therapy. Trials of these therapies in patients with cirrhosis have not been placebo controlled so that the rate of spontaneous hepatic decompensation in patients with cirrhosis due to hepatitis C is not well defined. Whatever the reason, the occurrence of decompensation in up to 10% of patients with cirrhosis undergoing potent antiviral therapy makes prospective monitoring advisable and prompt discontinuation of treatment if evidence of hepatic failure supervenes. Thus, the five antiviral compounds included in Viekira Pak regimens (dasabuvir, ombitasvir, paritaprevir, ritonavir and ribavirin) have been linked to instances of sudden ALT elevations during therapy, but uncommonly to clinically apparent liver injury. In patients with preexisting cirrhosis, antiviral therapy with Viekira Pak has been linked to episodes of lactic acidosis and hepatic decompensation. The cause of these sudden, severe adverse events is unknown but they are usually severe and life threatening, requiring prompt discontinuation of treatment, intensive care management and consideration of emergency liver transplantation. Likelihood score: C (probable cause of liver injury arising in patients with pre-existing cirrhosis).

来源:LiverTox

毒理性

• 蛋白质结合

97至98.6%与人血浆蛋白结合【FDA标签】。

97 to 98.6% bound to human plasma proteins [FDA Label].

来源:DrugBank

吸收、分配和排泄

• 吸收

大约4到5小时达到最高血药浓度（Cmax）194 ng/mL [美国食品药品监督管理局标签]。

Tmax of approximately 4 to 5 hours with a maximum concentration (Cmax) of 194 ng/mL [FDA Label].

来源:DrugBank

吸收、分配和排泄

• 消除途径

在单次给药14C-帕里他普韦与100毫克利托那韦联合使用后，大约88%的放射性物质在粪便中回收，尿液中有限的放射性物质（8.8%）；未改变的帕里他普韦在粪便中的放射性物质占1.1%，在尿液中的放射性物质占0.05% [FDA标签]。

Following a single dose administration of 14C-paritaprevir co-dosed with 100 mg of ritonavir, approximately 88% of the radioactivity was recovered in feces with limited radioactivity (8.8%) in urine; unchanged paritaprevir accounted for 1.1% of the radioactivity in the feces and 0.05% in the urine [FDA Label].

来源:DrugBank

吸收、分配和排泄

• 分布容积

稳态分布容积大约为103升（美国食品药品监督管理局标签）。

Volume of distribution at steady state is approximately 103 L [FDA Label].

来源:DrugBank

安全信息

• 储存条件：
  -20℃

制备方法与用途

生物活性

Paritaprevir（ABT-450）是一种NS3/4A抑制剂。

靶点

Target	Value
HCV genotype 1b (in replicon cell culture assays)	0.21 nM(EC50)
HCV genotype 1a (in replicon cell culture assays)	1 nM(EC50)

体外研究

在体外，Paritaprevir可抑制p-gp。Paritaprevir（ABT-450）是一种有效的HCV NS3/4A蛋白酶抑制剂，对含有NS3蛋白酶基因型1a、1b、2a、3a、4a和6a的稳定型HCV复制子EC50分别为1、0.21、5.3、19、0.09和0.69 nM。ABT-450的CC50大于37 μM，体外选择性指数大于37,000倍。它对多种HCV基因型具有活性，对基因型2a的JFH-1亚基因复制子细胞的EC50为5.3 nM。

体内研究

通过口服途径，Paritaprevir在4-5小时内达到最大血药浓度，药物暴露水平的增加超过剂量比例。与食物一起给药时，其口服生物利用度约为50%。在体内，Paritaprevir具有高血浆蛋白结合率，表观分布容积为16.7 L。它主要通过CYP3A4和CYP3A5代谢。

反应信息

• 作为反应物：
  描述：

  帕利普韦 在 human recombinant CYP₃A₄ 作用下， 以 aq. phosphate buffer 、 乙醇 为溶剂， 生成
  参考文献：
  名称：

  Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro

  摘要：

  Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3 or CYP3A5*3/*3. The intrinsic clearance (CLint, V-max/K-m) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.

  DOI：

  10.1080/00498254.2018.1524947
• 作为产物：
  描述：

  5-甲基吡嗪-2-羧酸 、 Paritaprevir metabolite M25 在 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 以11.15 kg的产率得到帕利普韦
  参考文献：
  名称：

  一种原料药帕利普韦的制备方法

  摘要：

  本发明公开了一种原料药帕利普韦的制备方法，包括中间体1‑(4‑(叔丁基苯基)‑2,5‑双(4‑硝基苯基))吡咯烷中双硝基的还原反应S1、双氨基的脯氨酸肽耦合反应S2和吡咯烷氨基的脱保护反应S3以及吡咯烷氨基的缬氨酸肽耦合反应S4。本发明原料药帕利普韦的制备方法中采用中间体Ⅰ作为原料，经闭环、氨基脱保护和酰胺化制得帕利普韦，步骤简单，反应条件温和，中间产物稳定性高，中间体分离收率高，反应体系溶剂均可实现回收再利用，上述因素均有利于工业化大规模生产。

  公开号：

  CN107383021A

文献信息

• TOLL LIKE RECEPTOR MODULATOR COMPOUNDS
  申请人：Gilead Sciences, Inc.

  公开号：US20180065938A1

  公开（公告）日：2018-03-08

  This application relates generally to toll like receptor modulator compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR8), and methods of making and using them.

  该应用程序通常涉及调节Toll样受体调节剂化合物和药物组合物，这些化合物在其他方面调节Toll样受体（例如TLR8），以及制备和使用它们的方法。
• PROCESS FOR MAKING HCV PROTEASE INHIBITORS
  申请人：ABBVIE INC.

  公开号：US20130178630A1

  公开（公告）日：2013-07-11

  Efficient processes for making HCV protease inhibitors are described. In one embodiment, the process uses novel idazolide derivatives of vinyl-ACCA.

  描述了制造HCV蛋白酶抑制剂的高效过程。在一种实施例中，该过程使用了新型咪唑酰乙烯基-ACCA衍生物。
• Macrocyclic hepatitis C serine protease inhibitors
  申请人：Ku Yiyin

  公开号：US20100144608A1

  公开（公告）日：2010-06-10

  The present invention relates to novel macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.

  本发明涉及新型大环化合物及其用于治疗需要该治疗的丙型肝炎感染患者的方法。本发明还涉及包含本发明化合物或其药学上可接受的盐、酯或前药与药学上可接受的载体或赋形剂组合的制药组合物。
• Mono (PSI-7977) or combination treatment of DAAs for use in treating HCV
  申请人：Abbvie Inc.

  公开号：EP2583680A2

  公开（公告）日：2013-04-24

  The present invention features interferon- and ribavirin-free therapies for the treatment of HCV. Preferably, the treatment is over a shorter duration of treatment, such as no more than 12 weeks. In one aspect, the therapies comprise administering at least two direct acting antiviral agents without interferon and ribavirin to a subject with HCV infection. For example, the therapies comprise administering to a subject an effective amounts of BMS-790052 (daclatasvir) and BMS-650032 (asunaprevir) and an inhibitor of cytochrome P450 (e.g., ritonavir).

  本发明涉及治疗丙型肝炎的干扰素和利巴韦林自由疗法。最好的情况下，治疗的时间更短，如不超过12周。在一方面，该疗法包括向患有丙型肝炎感染的个体施用至少两种直接作用抗病毒药物，而不需要干扰素和利巴韦林。例如，该疗法包括向个体施用有效剂量的BMS-790052（达克拉他韦）和BMS-650032（阿索那普韦）以及细胞色素P450的抑制剂（例如利托那韦）。
• MACROCYCLIC HEPATITIS C SERINE PROTEASE INHIBITORS
  申请人：Ku Yiyin

  公开号：US20120196792A1

  公开（公告）日：2012-08-02

  The present invention relates to novel macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.

  本发明涉及新型大环化合物及使用该大环化合物治疗需要此类治疗的乙型肝炎感染患者的方法。本发明还涉及含有本发明化合物或其药学上可接受的盐、酯或前药的制药组合物，与药学上可接受的载体或赋形剂结合使用。