Tecovirimat | 869572-92-9

• 物质功能分类: 原料药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: Tecovirimat
• 英文别名: N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1 ,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)benzamide；N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl)-benzamide；N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-4-(trifluoromethyl)benzamide；ST-246；4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide；N-[(1S,2S,6R,7R,8R,10S)-3,5-dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-yl]-4-(trifluoromethyl)benzamide
• CAS: 869572-92-9
• 化学式: C₁₉H₁₅F₃N₂O₃
• 分子量: 376.335
• InChiKey: CSKDFZIMJXRJGH-VWLPUNTISA-N

物化性质

• 熔点：
  194-195 °C
• 密度：
  1.53±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  27
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  66.5
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

体外研究表明，tecovirimat不是主要细胞色素P450（CYP）酶的底物，但它是人类重组UGT酶（特别是UGT1A1和1A4）的底物[FDA标签]。Tecovirimat被发现代谢为3种最丰富的代谢物，M4、M5和TFMBA，这些代谢物没有药理活性[FDA标签]。

In vitro studies indicate that tecovirimat is not a substrate of major cytochrome P450 (CYP) enzymes, but it is a substrate of human recombinant UGTs (specifically of UGT1A1 and 1A4) [FDA label]. Tecovirimat was found to be metabolized into 3 most abundant metabolites, M4, M5 and TFMBA, which do not have pharmacological activity [FDA label].

来源:DrugBank

毒理性

• 毒性总结

tecovirimat 显示出良好的耐受性，没有严重的不良事件（AEs）。健康成年受试者（≥2%）常见的不良反应包括头痛、恶心、腹痛和呕吐[FDA 标签]，[A35143]。repaglinide 和 tecovirimat 联合使用可能会导致轻到中度的低血糖[FDA 标签]。口服 tecovirimat 在剂量水平高达 2,000 mg/kg/天（小鼠）时通常具有良好的耐受性[F619]。

Tecovirimat has demonstrated to be well tolerated, with no serious adverse events (AEs). Common adverse reactions in healthy adult subjects (≥ 2%) were headache, nausea, abdominal pain, and vomiting [FDA label], [A35143]. Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia [FDA label]. Oral administration of tecovirimat is generally well-tolerated at dose levels up to 2,000 mg/kg/day (mice) [F619].

来源:DrugBank

毒理性

• 蛋白质结合

大约80%。

Approximately 80% [F619].

来源:DrugBank

吸收、分配和排泄

• 吸收

容易经口服给药后吸收，平均达到最高浓度的时间为3到4小时[A35133]。进行了一项研究，以确定ST-246作为单日口服剂量给药的安全性、耐受性和药代动力学。稳态在第6天达到（在3到5个半衰期之内）[A35134]。

Readily absorbed following oral administration, with mean times to maximum concentration from 3 to 4 h [A35133]. A study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose. Steady state was reached by day 6 (within 3 to 5 half-lives)[A35134].

来源:DrugBank

吸收、分配和排泄

• 消除途径

药物在肾脏中以未改变的形式排泄的比例小于0.02%，大部分药物以葡萄糖醛酸化的形式排泄。大约23%的未改变药物在粪便中找到 [F619]。

Less than 0.02% of the drug is excreted unchanged in the kidney, with a majority of the drug being excreted in glucuronidated form. Approximately 23% of unchanged drug is found in the feces [F619].

来源:DrugBank

吸收、分配和排泄

• 分布容积

大约1,356升。在小鼠口服给药后，[14C]-tecovirimat 分布到所有被分析的组织中，其中肝脏和胆囊、呼吸道组织（即鼻甲）和骨髓中的浓度最高。在狗和非人灵长类动物（NHPs）的研究表明，tecovirimat 能够穿过血脑屏障。

Approximately 1,356 L. Following oral administration in mice, [14C]-tecovirimat was distributed to all tissues analyzed with the highest concentrations noted in liver and gallbladder, respiratory tract tissues (i.e., nasal turbinates), and bone marrow. Studies in dogs and NHPs suggest that tecovirimat crosses the blood-brain barrier [F619].

来源:DrugBank

吸收、分配和排泄

• 清除

主要是肾脏[F619]。

Mainly renal [F619].

来源:DrugBank

制备方法与用途

生物活性

Tecovirimat（AreSTvyr、SIGA-246、ST-246、TPOXX）是一种抗病毒药物，通过靶向正痘病毒的p37蛋白同源物来抑制病毒释放。该药物主要用于治疗天花感染。

靶点

Target	Value
p37 protein ortholog	()

反应信息

• 作为产物：
  描述：

  4-(三氟甲基)亚苯基肼 以 邻二甲苯 、 甲苯 为溶剂， 反应 44.5h， 生成 Tecovirimat
  参考文献：
  名称：

  [EN] METHODS OF PREPARING TECOVIRIMAT
  [FR] PROCÉDÉ DE PRÉPARATION DE TECOVIRIMAT

  摘要：

  公开了用于制备Tecovirimat以治疗或预防病毒感染及相关疾病的方法，尤其是由正痘病毒引起的病毒感染和相关疾病。

  公开号：

  WO2014028545A1

文献信息

• PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT AND PREVENTION OF ORTHOPOXVIRUS INFECTIONS AND ASSOCIATED DISEASES
  申请人：Siga Technologies, Inc.

  公开号：EP3006425A1

  公开（公告）日：2016-04-13

  Pharmaceutical compositions containing di, tri, and tetracyclic acylhydrazide derivatives of the formula below, for use in the treatment or prophylaxis of viral infections and diseases associated therewith, particularly those viral infections and associated diseases caused by the orthopoxvirus.

  含有以下结构的二、三和四环脂肼衍生物的药物组合物，用于治疗或预防病毒感染及相关疾病，特别是由正痘病毒引起的那些病毒感染和相关疾病。
• Polymorphic Forms of ST-246 and Methods of Preparation
  申请人：Tyavanagimatt Shanthakumar R.

  公开号：US20110236434A1

  公开（公告）日：2011-09-29

  Polymorph forms of 4-trifluoromethyl-N-(3,3 a ,4,4 a ,5,5 a ,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide are disclosed as well as their methods of synthesis and pharmaceutical compositions.

  本发明公开了4-三氟甲基-N-(3,3a,4,4a,5,5a,6,6a-八氢-1,3-二氧杂环丙基[f]异吲哚-2(1H)-基)-苯甲酰胺的多态形式，以及它们的合成方法和制备的药物组合物。
• [EN] COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT AND PREVENTION OF ORTHOPOXVIRUS INFECTIONS AND ASSOCIATED DISEASES<br/>[FR] COMPOSES, COMPOSITIONS ET PROCEDES PERMETTANT DE TRAITER ET DE PREVENIR DES INFECTIONS A ORTHOPOXVIRUS ET DES MALADIES ASSOCIEES
  申请人：VIROPHARMA INC

  公开号：WO2004112718A2

  公开（公告）日：2004-12-29

  Methods of using di, tri, and tetracyclic acylhydrazide derivatives and analogs, as well as pharmaceutical compositions containing the same, for the treatment or prophylaxis of viral infections and diseases associated therewith, particularly those viral infections and associated diseases cased by the orthopoxvirus.

  使用二、三、四环酰肼衍生物及类似物的方法，以及含有其的药物组合物，用于治疗或预防病毒感染及其相关疾病，特别是由正痘病毒引起的病毒感染和相关疾病。
• Chemicals, compositions, and methods for treatment and prevention of orthopoxvirus infections and associated diseases
  申请人：Jordan F. Robert

  公开号：US20070287735A1

  公开（公告）日：2007-12-13

  Methods of using di, tri, and tetracyclic acylhydrazide derivatives and analogs, as well as pharmaceutical compositions containing the same, for the treatment or prophylaxis of viral infections and diseases associated therewith, particularly those viral infections and associated diseases cased by the orthopoxvirus.

  使用二、三和四环戊二酰肼衍生物及类似物的方法，以及含有它们的药物组合物，用于治疗或预防病毒感染及其相关疾病，特别是由正痘病毒引起的病毒感染和相关疾病。
• COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT AND PREVENTION OF ORTHOPOXVIRUS INFECTIONS AND ASSOCIATED DISEASES
  申请人：Jordan Robert

  公开号：US20120020922A1

  公开（公告）日：2012-01-26

  Methods of using di, tri, and tetracyclic acylhydrazide derivatives and analogs, as well as pharmaceutical compositions containing the same, for the treatment or prophylaxis of viral infections and diseases associated therewith, particularly those viral infections and associated diseases caused by the orthopoxvirus.

  使用二、三、四环腈肟衍生物及类似物的方法，以及包含它们的制药组合物，用于治疗或预防病毒感染及其相关疾病，特别是由正痘病毒引起的病毒感染和相关疾病。