维帕他韦 | 1377049-84-7

• 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 - 有机杂环化合物 - 萘并吡喃类
• 中文名称: 维帕他韦
• 中文别名: 韦帕它韦；韦帕他韦；GS-5816；沃帕他韦
• 英文名称: velpatasvir
• 英文别名: methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate；methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate；Velpatasvir；methyl N-[(1R)-2-[(2S,4S)-2-[5-[6-[(2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-5-methylpyrrolidin-2-yl]-21-oxa-5,7-diazapentacyclo[11.8.0.03,11.04,8.014,19]henicosa-1(13),2,4(8),5,9,11,14(19),15,17-nonaen-17-yl]-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl]carbamate
• CAS: 1377049-84-7
• 化学式: C₄₉H₅₄N₈O₈
• 分子量: 883.017
• InChiKey: FHCUMDQMBHQXKK-CDIODLITSA-N

物化性质

• 熔点：
  >170oC (dec.)
• 密度：
  1.314±0.06 g/cm3(Predicted)
• 溶解度：
  溶于DMSO(>25mg/ml)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  65
• 可旋转键数：
  13
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  193
• 氢给体数：
  4
• 氢受体数：
  10

ADMET

代谢

一些代谢由CYP2B6、CYP2C8和CYP3A4进行。

Some metabolism by CYP2B6, CYP2C8, and CYP3A4.

来源:DrugBank

毒理性

• 毒性总结

无致癌性或对生育能力/胎儿存活能力影响的迹象。

No indication of carcinogenicity or impairment of fertility/fetal viability.

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，索非布韦是与其他抗病毒药物（如聚乙二醇干扰素、西美瑞韦、达卡他韦或雷迪帕韦）联合使用的，索非布韦的具体作用一直难以界定。这种衰竭通常与快速病毒清除同时发生，而经历过这一事件的幸存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，这种损伤可能是巧合的，与治疗无关。 第二种可能在索非布韦治疗中发生的肝损伤形式，也可能与其他强效抗HCV药物有关，是乙型肝炎的再激活。在慢性丙型肝炎且HBsAg阳性、HBV DNA水平低的患者中，已经报告了临床明显的肝炎和血清HBV DNA水平升高的病例，这些水平不被认为是慢性肝病的原因（案例2）。在HBsAg阴性、血清中抗HBc阳性的患者中，也描述了再激活，这种情况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后的2到8周内出现，并且可以以急性肝炎的症状、血清转氨酶水平和胆红素的显著升高为临床表现。已经报告了在索非布韦治疗中因HBV再激活而死亡的病例。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，由于突然清除HCV或抗病毒药物的直接活性，免疫反应性的改变可能改变HBV的复制状态。 可能性评分：E*（在易感个体中未经证实但疑似是临床明显肝损伤的原因）。

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. Likeli