voxilaprevir | 1535212-07-7

• 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
• 英文名称: voxilaprevir
• 英文别名: (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1 R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,1 0,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide；Voxilaprevir；(1R,18R,20R,24S,27S,28S)-24-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropyl)sulfonylcarbamoyl]cyclopropyl]-28-ethyl-13,13-difluoro-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetrazapentacyclo[24.2.1.03,12.05,10.018,20]nonacosa-3,5(10),6,8,11-pentaene-27-carboxamide
• CAS: 1535212-07-7
• 化学式: C₄₀H₅₂F₄N₆O₉S
• 分子量: 868.947
• InChiKey: MZBLZLWXUBZHSL-FZNJKFJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.96
• 重原子数：
  60.0
• 可旋转键数：
  8.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  195.22
• 氢给体数：
  3.0
• 氢受体数：
  11.0

ADMET

代谢

伏西拉普韦主要经细胞色素P450 3A4（CYP3A4）代谢，其次较少程度地通过CYP2C8和CYP1A2代谢。

Voxilaprevir is primarily metabolized by Cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2C8 and CYP1A2.

来源:DrugBank

毒理性

• 肝毒性

在大规模随机对照试验中，尽管接受索非布韦治疗的患者患有慢性肝病，但血清酶升高的情况并不常见。在大多数情况下，开始索非布韦治疗时，血清转氨酶水平会迅速改善，而且新的、晚期ALT升高超过正常上限3倍的情况并不常见，比安慰剂或不治疗的情况要少。在多个大型临床试验中，索非布韦并未与黄疸的临床明显肝损伤病例有关联。因为索非布韦总是与其他抗病毒药物一起使用，所以不可能总是将索非布韦与其他药物在引起不良反应中的相对作用区分开来。 有两种罕见且不寻常的与索非布韦关系不明的肝损伤形式在用抗病毒治疗丙型肝炎的患者中被描述：突然肝功能衰竭的患者有预先存在的肝硬化，以及在有预先存在的HBV感染证据的患者中乙型肝炎的再激活。 与索非布韦（也许还有其他对HCV有效的强效药物）相关的一种罕见但显著的肝损伤是在预先存在肝硬化的患者中发生的肝功能衰竭。在几个实例中，肝功能衰竭在开始治疗后的2到6周内发生（案例1），而在其他情况下，它发生在治疗晚期或治疗结束后的立即期。发病的典型模式是胆红素逐渐升高，伴有肝衰竭的迹象，如凝血酶原时间延长、血清白蛋白下降和腹水和肝性脑病的出现。在许多（但不是所有）实例中，与治疗前相比，血清酶水平没有变化或仅略有升高。在所有实例中，索非布韦与其他抗病毒药物（如聚乙二醇干扰素、西美瑞韦、达卡他韦或雷迪帕韦）联合使用，索非布韦的具体作用难以界定。肝功能衰竭通常与病毒的快速清除同时发生，而幸存下来的患者通常会有持续的病毒学应答。这种衰竭的原因尚不清楚，但它可能代表了对HCV病毒根除的反应（靶上效应），而不是所给予抗病毒剂的毒性（对肝脏的靶外效应）。或者，这种损伤可能是偶然的，与治疗无关。 第二种可能在索非布韦治疗和其他强效抗HCV药物时发生的肝损伤形式是乙型肝炎的再激活。在HBsAg阳性、HBV DNA水平低、不被认为是慢性肝病原因的慢性丙型肝炎患者中，出现了临床上明显的肝炎和血清HBV DNA水平升高的实例（案例2）。在抗HBc阳性但血清中无HBsAg的患者中，也描述了再激活，这种模式表明之前从乙型肝炎中恢复。HBV再激活通常在开始治疗丙型肝炎的2到8周内出现，并且可能临床上表现为急性肝炎的症状、血清转氨酶水平和胆红素显著升高。有报道称，在使用索非布韦治疗期间，有因HBV再激活而死亡的实例。再激活的原因尚不清楚，但它可能反映了HCV复制的根除，HCV复制对HBV复制有非特异性的抑制作用。或者，随着HCV的突然清除或由于抗病毒剂的直接作用，免疫反应性的改变可能会改变HBV的复制状态。 可能性评分：E*（在易感个体中未被证实但疑似是临床上明显肝损伤的原因）。

In large randomized controlled trials, serum enzymes elevations were uncommon in patients treated with sofosbuvir despite the fact that the patients being treated had chronic liver disease. In most situations, serum aminotransferase levels improved rapidly upon initiating sofosbuvir therapy, and de novo, late elevations of ALT above 3 times the upper limit of normal (ULN) were uncommon and less frequent than with placebo or no therapy. In multiple, large clinical trials sofosbuvir has not been linked to instances of clinically apparent liver injury with jaundice. Because sofosbuvir is always used with other antiviral agents, it is not always possible to separate the relative role of sofosbuvir from other drugs in causing adverse reactions. Two rare and unusual forms of liver injury of uncertain relationship to sofosbuvir have been described in patients with receiving antiviral therapy for hepatitis C: sudden hepatic decompensation in patients with preexisting cirrhosis and reactivation of hepatitis B in patients with preexisting evidence of HBV infection. A rare, but striking liver injury associated with sofosbuvir (and perhaps other potent agents active against HCV) is hepatic decompensation occurring in patients with preexisting cirrhosis. In several instances, decompensation occurred within 2 to 6 weeks of starting therapy (Case 1), while in others it occurred late during therapy or in the immediate posttreatment period. The typical pattern of onset was a progressive rise in bilirubin with signs of hepatic failure such as prolongation of the prothrombin time, decrease in serum albumin and appearance of ascites and hepatic encephalopathy. In many (but not all) instances, serum enzyme levels did not change or increased only slightly in comparison to pretreatment values. In all instances, sofosbuvir was being used in combination with other antiviral agents, such as peginterferon, simeprevir, daclatasvir or ledipasvir, and the specific role of sofosbuvir has been difficult to define. The decompensation usually coincided with rapid viral clearance and patients who survived the episode often had a sustained virological response. The cause of this decompensation is not clear, but it may represent a response to HCV viral eradication (on-target effect) rather than toxicity of the administered antiviral agents (off-target effect on the liver). Alternatively, the injury may be coincidental and unrelated to therapy. A second form of liver injury that can occur with sofosbuvir therapy and perhaps other potent anti-HCV agents is reactivation of hepatitis B. Instances of clinically apparent hepatitis with rises in serum HBV DNA levels have been reported in patients with chronic hepatitis C who were HBsAg positive and had low levels of HBV DNA which were not thought to be the cause of the chronic liver disease (Case 2). Reactivation has also been described in patients who have anti-HBc without HBsAg in serum, a pattern that suggests previous recovery from hepatitis B. HBV reactivation typically arises within 2 to 8 weeks of starting therapy for hepatitis C and it can be clinically manifest with symptoms of acute hepatitis and marked elevations in serum aminotransferase levels and bilirubin. Instances of death from HBV reactivation have been reported with sofosbuvir therapy. The cause of reactivation is unclear, but it may reflect the eradication of HCV replication which has a nonspecific suppressive effect on HBV replication. Alternatively, the change in immune reactivity with sudden clearance of HCV or as a result of a direct activity of the antiviral agents may alter the replicative status of HBV. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury in susceptible individuals).

来源:LiverTox

毒理性

• 蛋白质结合

伏西拉普韦（Voxilaprevir）与人类血浆蛋白的结合率超过99%。

Voxilaprevir is more than 99% bound to human plasma proteins.

来源:DrugBank

吸收、分配和排泄

• 吸收

当与[DB08934]和[DB11613]一起作为固定剂量组合产品Vosevi提供时，voxilaprevir在服用后4小时达到最大浓度（Cmax）192 ng/mL。

When provided as the fixed dose combination product Vosevi with [DB08934] and [DB11613], voxilaprevir reaches a maximum concentration (Cmax) of 192 ng/mL at a maximum time (Tmax) of 4 hours post-dose.

来源:DrugBank

吸收、分配和排泄

• 消除途径

伏西拉普韦主要通过胆汁排泄消除。

Voxilaprevir is primarily eliminated via biliary excretion.

来源:DrugBank

安全信息

• 储存条件：
  2-8°C

制备方法与用途

Voxilaprevir（GS-9857）是一种含氟大环丙型肝炎病毒(HCV)非结构蛋白(NS)3/4A蛋白酶抑制剂，对基因型1至6的HCV具有很强的体外抗病毒活性，并广泛覆盖NS3/4A蛋白酶多态性。此外，GS-9857还提高了对常见NS3抗药性相关突变体(RAVs)的覆盖率。

反应信息

• 作为产物：
  描述：

  (S)-3,3-二甲基-2-((((1R,2R)-2-(戊-4-烯-1-基)环丙氧基)羰基)氨基)丁酸 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 sodium periodate 、 四氧化锇 、 2-硝基苯基丝氰酸酯 、 三丁基膦 、 詹氏催化剂 、 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 100.0 ℃ 、101.33 kPa 条件下， 反应 87.92h， 生成 voxilaprevir
  参考文献：
  名称：

  [EN] INHIBITORS OF HEPATITIS C VIRUS
  [FR] INHIBITEURS DU VIRUS DE L'HÉPATITE C

  摘要：

  化合物I的结构已经披露，以及其药用盐。还披露了使用这些化合物的方法和含有这些化合物的药物组合物。

  公开号：

  WO2014008285A1

文献信息

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

  公开号：US20160289229A1

  公开（公告）日：2016-10-06

  The present disclosure relates generally to toll like receptor modulator compounds, such as diamino pyrido[3,2 D]pyrimidine compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR-8), and methods of making and using them.

  本公开涉及调节类似受体调节剂化合物，例如二氨基吡啶并[3,2 D]嘧啶化合物和药物组合物，其中调节类似受体（例如TLR-8），以及制备和使用它们的方法。
• ANTIVIRAL COMPOUNDS
  申请人：Gilead Sciences, Inc.

  公开号：US20150361087A1

  公开（公告）日：2015-12-17

  The disclosure is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  该披露涉及抗病毒化合物，含有这种化合物的组合物，包括给予这种化合物的治疗方法，以及用于制备这种化合物的有用过程和中间体。
• [EN] 4,6-DIAMINO-PYRIDO[3,2-D]PYRIMIDINE DERIVATIES AS TOLL LIKE RECEPTOR MODULATORS<br/>[FR] DÉRIVÉS DE 4,6-DIAMINO-PYRIDO [3,2-D] PYRIMIDINE EN TANT QUE MODULATEURS DU RÉCEPTEUR DE TYPE TOLL
  申请人：GILEAD SCIENCES INC

  公开号：WO2018045150A1

  公开（公告）日：2018-03-08

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

  本申请一般涉及如下面定义的Toll样受体调节剂化合物以及药用组合物，它们在其他方面中调节Toll样受体（例如TLR8），以及它们的制备和使用方法。
• Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi®
  作者：James G. Taylor、Sheila Zipfel、Kyla Ramey、Randy Vivian、Adam Schrier、Kapil K. Karki、Ashley Katana、Darryl Kato、Tetsuya Kobayashi、Ruben Martinez、Michael Sangi、Dustin Siegel、Chinh V. Tran、Zheng-Yu Yang、Jeff Zablocki、Cheng Y. Yang、Yujin Wang、Kelly Wang、Katie Chan、Ona Barauskas、Guofeng Cheng、Debi Jin、Brian E. Schultz、Todd Appleby、Armando G. Villaseñor、John O. Link

  DOI：10.1016/j.bmcl.2019.03.037

  日期：2019.8

  therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further

  丙型肝炎病毒（HCV）感染的治疗历来具有挑战性，原因是病毒遗传复杂性高，其中有八种不同的基因型和至少86种病毒亚型。虽然HCV NS3 / 4A蛋白酶抑制剂是基因1型感染的既定治疗选择，但对于某些化合物而言，基因2型和/或3型覆盖率有限以及血清丙氨酸转氨酶（ALT）升高，限制了该治疗类别的广泛应用。我们的发现工作集中在鉴定具有泛基因型抗病毒活性，抗药性相关替代物的覆盖率提高以及肝毒性风险降低的NS3 / 4A蛋白酶抑制剂上。为了实现这一目标，已确定了与保守的NS3 / 4A蛋白酶催化三联体的独特相互作用，从而改善了基因型3的抗病毒活性。我们进一步发现，对于这种治疗类别，蛋白质加合物的形成与临床ALT升高密切相关。通过结构修饰改善代谢稳定性并减少蛋白质加合物的形成最终产生了voxilaprevir。Voxilaprevir与sofosbuvir和velpatasvir的组合已证明具有泛基因型
• SYNTHESIS OF AN ANTIVIRAL COMPOUND
  申请人：Cagulada Amy

  公开号：US20150175626A1

  公开（公告）日：2015-06-25

  The present disclosure provides processes for the preparation of a compound of formula I: which is useful as an antiviral agent. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.

  本公开提供了一种制备式I化合物的方法，该化合物可用作抗病毒剂。本公开还提供了用于制备化合物的方法和化合物，这些化合物是式I化合物的合成中间体。