fostemsavir | 864953-29-7

• 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 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: fostemsavir
• 英文别名: BMS-663068-03；[3-[(4-benzoylpiperazin-1-yl)(oxo)acetyl]-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate；1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine；[3-[2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate
• CAS: 864953-29-7
• 化学式: C₂₅H₂₆N₇O₈P
• 分子量: 583.497
• InChiKey: SWMDAPWAQQTBOG-UHFFFAOYSA-N

物化性质

• 沸点：
  904.1±75.0 °C(Predicted)
• 密度：
  1.60±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)：
  -0.1
• 重原子数：
  41
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  182
• 氢给体数：
  2
• 氢受体数：
  11

ADMET

代谢

Fostemsavir迅速被肠道腔内刷状缘膜上的碱性磷酸酶水解为其活性代谢物temsavir。Temsavir进一步转化为两种主要的无活性代谢物：BMS-646915，由酯酶水解产生，以及BMS-930644，通过CYP3A4氧化生成的N-脱烷基代谢物。大约36.1%的口服剂量通过酯酶代谢，21.2%通过CYP3A4代谢，少于1%在消除前通过UDP-葡萄糖醛酸基转移酶（UGT）进行结合。Temsavir及其两种主要代谢物均已知可抑制BCRP。

Fostemsavir is rapidly hydrolyzed to temsavir, its active metabolite, by alkaline phosphatase(s) present at the brush border membrane of the intestinal lumen. Temsavir undergoes further biotransformation to two predominant inactive metabolites: BMS-646915, a product of hydrolysis by esterases, and BMS-930644, an N-dealkylated metabolite generated via oxidation by CYP3A4. Approximately 36.1% of an administered oral dose is metabolized by esterases, 21.2% is metabolized by CYP3A4, and <1% is conjugated by UDP-glucuronosyltransferases (UGT) prior to elimination. Both temsavir and its two predominant metabolites are known to inhibit BCRP.

来源:DrugBank

毒理性

• 肝毒性

在注册临床试验中，fostemsavir与丙氨酸氨基转移酶（ALT）升高有关，高达25%的患者出现这种情况，但仅有4%的受试者ALT水平超过正常上限的5倍。大多数ALT升高是短暂的、无症状的，不需要调整剂量或停药。更显著的ALT升高通常归因于其他条件或HIV感染的并发症。在预注册试验中没有观察到由fostemsavir引起的肝损伤的明确案例。自从fostemsavir被批准作为多药治疗HIV的一部分以来，没有发表过归因于其使用的临床明显肝损伤的案例报告。 有趣的是，在fostemsavir的大型预注册试验中，尤其是那些同时感染乙型肝炎病毒（HBV）或丙型肝炎病毒（HCV）的患者中，血清转氨酶水平的升高特别明显。在这项试验中，由于治疗期间合并感染恶化导致的肝病死亡病例。显然，HBV或HCV合并感染的患者应在接受fostemsavir抗逆转录病毒治疗之前或同时治疗这些病毒感染。 可能性评分：E*（未证实但疑似是临床明显肝损伤的原因）。

In registration clinical trials, fostemsavir was associated with alanine aminotransferase (ALT) elevations in up to 25% of patients, but levels above 5 times the upper limit of normal (ULN) arose in only 4% of subjects. Most ALT elevations were transient, asymptomatic, and did not require dose modification or discontinuation. The more marked ALT elevations were usually attributable to other conditions or complications of HIV infection. No convincing cases of fostemsavir induced liver injury were observed in preregistration trials. Since approval of fostemsavir for use as a part of a multidrug therapy of HIV, there have been no published case reports of clinically apparent liver injury attributed to its use. Interestingly, in the large preregistration trial of fostemsavir, elevations in serum aminotransferase levels were particularly noted in patients with coinfection with either hepatitis B virus (HBV) or hepatitis C virus (HCV). The deaths from liver disease in this trial appeared to be due to worsening of the coinfection during therapy. Clearly, patients with HBV or HCV coinfection should be treated for those viral infections before or concurrent with antiretroviral therapy with fostemsavir. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 蛋白质结合

Temsavir在大约88.4%的血浆中与蛋白质结合，主要与血清白蛋白结合。

Temsavir is approximately 88.4% protein-bound in plasma, primarily to serum albumin.

来源:DrugBank

吸收、分配和排泄

• 吸收

特马昔韦的吸收受到口服给药后溶解度和溶解性不足的显著限制。福斯特马昔韦是特马昔韦的磷酰氧甲基前药，与母药相比，在水中的溶解度和酸性条件下的稳定性有所提高 - 口服福斯特马昔韦后，其绝对生物利用度约为26.9%。口服福斯特马昔韦600毫克，每日两次，其Cmax和AUCtau分别为1770 ng/mL和12,900 ng·h/L，Tmax大约为2小时。与标准餐同服福斯特马昔韦，其AUC增加约10%，而与高脂肪餐同服，其AUC增加约81%。

The absorption of temsavir is significantly limited by suboptimal dissolution and solubility following oral administration. Fostemsavir, a phosphonooxymethyl prodrug of temsavir, has improved aqueous solubility and stability under acidic conditions as compared to its parent drug - following oral administration of fostemsavir, the absolute bioavailability is approximately 26.9%. The Cmax and AUCtau following oral administration of fostemsavir 600mg twice daily was 1770 ng/mL and 12,900 ng.h/L, respectively, with a Tmax of approximately 2 hours. Co-administration of fostemsavir with a standard meal increases its AUC by approximately 10%, while co-administration with a high-fat meal increases its AUC by approximately 81%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Temsavir高度代谢，之后以无活性代谢物的形式在尿液和粪便中排出。大约51%的剂量通过尿液排出，其中不到2%为未改变的母药，而33%通过粪便排出，其中1.1%为未改变的母药。

Temsavir is highly metabolized, after which it is excreted in the urine and feces as inactive metabolites. Approximately 51% of a given dose is excreted in the urine, with <2% comprising unchanged parent drug, and 33% is excreted in the feces, of which 1.1% is unchanged parent drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药后，temsavir的稳态分布体积大约为29.5升。

The steady-state volume of distribution of temsavir following intravenous administration is approximately 29.5 L.

来源:DrugBank

吸收、分配和排泄

• 清除

坦萨维尔（福斯特萨维尔的活动代谢物）的平均清除率和表观清除率分别为17.9 L/h和66.4 L/h。

The mean clearance and apparent clearance of temsavir, the active metabolite of fostemsavir, are 17.9 L/h and 66.4 L/h, respectively.

来源:DrugBank

安全信息

• 储存条件：
  -20°C，密闭保存，置于干燥处

制备方法与用途

生物活性

Fostemsavir（BMS-663068，Rukobia）是BMS626529的膦酰氧甲基前药，是一种附着抑制剂，靶向HIV-1 gp120，并阻止其与CD4+ T细胞结合，对应的EC50值小于10 nM。

靶点

Target	Value
HIV-1 gp120 (Cell-free assay)	10 nM (EC50)

反应信息

• 作为反应物：
  描述：

  fostemsavir 在 水 作用下， 以 甲醇 为溶剂， 生成 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine dihydrate
  参考文献：
  名称：

  Crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine

  摘要：

  该即时披露提供了1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1-[(磷酸酯氧基)甲基]-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪的晶体形式，其盐和溶剂化物。本公开还普遍涉及包括该晶体形式的制药组合物，以及使用该晶体形式治疗HIV和/或艾滋病的方法，以及获得这种晶体形式的方法。

  公开号：

  US20070155702A1
• 作为产物：
  描述：

  (3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl di-tert-butyl phosphate 在 水 作用下， 以 丙酮 为溶剂， 反应 24.0h， 以83%的产率得到fostemsavir
  参考文献：
  名称：

  Prodrugs of piperazine and substituted piperidine antiviral agents

  摘要：

  这项发明提供了前药化合物I，其药物组成物以及它们在治疗HIV感染中的用途。 其中： X为C或N，但当X为N时，R1不存在； W为C或N，但当W为N时，R2不存在；V为C；E为氢或其药用可接受盐；以及 Y从以下组中选择： 此外，这项发明提供了制备前药化合物I的有用中间体化合物II。 其中： L和M独立地选自C1-C6烷基，苯基，苯甲基，三烷基硅基，-2,2,2-三氯乙氧基和2-三甲基硅基乙氧基的组。

  公开号：

  US20050209246A1

文献信息

• [EN] A PROCESS FOR PREPARING HALOGENATED AZAINDOLE COMPOUNDS USING BOROXINE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE COMPOSÉS D'AZAINDOLE HALOGÉNÉS FAISANT APPEL À LA BOROXINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2016100625A1

  公开（公告）日：2016-06-23

  A process for preparing halogenated azaindole compounds makes use of stable reagents including a brominating reagent, a boroxine and a sulfonic anhydride to enhance the selectivity and yield of the final product. In addition, the process is associated with various other advantages, including the ability to recycle reagents, cost reduction, and improved manufacturability.

  一种制备卤代氮吲哚化合物的过程利用稳定试剂，包括溴化试剂、硼氧化物和磺酸酐，以增强最终产品的选择性和产量。此外，该过程还具有各种其他优点，包括能够回收试剂、降低成本和改善可制造性。
• [EN] A PROCESS FOR PREPARING HALOGENATED AZAINDOLE COMPOUNDS USING PYBROP<br/>[FR] PROCÉDÉ DE PRÉPARATION DE COMPOSÉS D'AZA-INDOLE HALOGÉNÉ EN UTILISANT DU PYBROP
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2016100651A1

  公开（公告）日：2016-06-23

  A process for preparing halogenated azaindole compounds makes use of a brominating agent PyBroP, together with a dehydrating agent BSA to enhance the selectivity and improve the yield of the final product which is a piperazine prodrug useful as an antiviral.

  制备卤代氮杂吲哚化合物的方法利用溴化剂PyBroP，结合脱水剂BSA，以增强选择性并提高最终产物的产率，该产物是一种对抗病毒有用的哌嗪前药。
• [EN] METHODS OF MAKING HIV ATTACHMENT INHIBITOR PRODRUG COMPOUND AND INTERMEDIATES<br/>[FR] PROCÉDÉS DE FABRICATION DE COMPOSÉ PROMÉDICAMENT INHIBITEUR DE LA FIXATION DU VIH ET DE SES INTERMÉDIAIRES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2012106189A1

  公开（公告）日：2012-08-09

  A method for making the compound of Formula ( I ) is set forth using alkylation, amidation, chlorination and phosphate installation procedures.

  使用烷基化、酰胺化、氯化和磷酸酯安装程序制备化合物式（I）的方法已经阐明。
• [EN] COMPOUNDS FOR THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS<br/>[FR] COMPOSÉS POUR LE TRAITEMENT DU VIRUS DE L'IMMUNODÉFICIENCE HUMAINE
  申请人：UNIV PENNSYLVANIA

  公开号：WO2021067528A1

  公开（公告）日：2021-04-08

  The present disclosure provides compounds of Formula (I) or pharmaceutically acceptable salts thereof: (I) wherein, R1 to R6 and X are defined herein. Also provided are pharmaceutical compositions comprising these compounds, methods for treating Human Immunodeficiency Virus (HIV-1) in a subject in need thereof using these compounds or pharmaceutical compositions, and methods for stabilizing the state- 1 conformation of the HIV-1 envelope glycoproteins using these compounds or pharmaceutical compositions.

  本公开提供公式（I）的化合物或其药学上可接受的盐：（I）其中，R1至R6和X在此被定义。还提供包含这些化合物的药物组合物，使用这些化合物或药物组合物治疗需要的人类免疫缺陷病毒（HIV-1）的方法，以及使用这些化合物或药物组合物稳定HIV-1包膜糖蛋白的状态-1构象的方法。
• METHODS FOR THE PREPARATION OF HIV ATTACHMENT INHIBITOR PIPERAZINE PRODRUG COMPOUND
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20150038711A1

  公开（公告）日：2015-02-05

  A method for making the compound is set forth utilizing the starting material

  利用起始材料制备化合物的方法被阐述。