hexadecyloxypropyl-cidofovir | 444805-28-1

• 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 - 二嗪类
• 英文名称: hexadecyloxypropyl-cidofovir
• 英文别名: phosphonic acid [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester；1-O-hexadecyloxypropylcidofovir；hexadecyloxypropyl cidofovir；brincidofovir；CMX-001；HDP-CDV；[(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid
• CAS: 444805-28-1
• 化学式: C₂₇H₅₂N₃O₇P
• 分子量: 561.7
• InChiKey: WXJFKKQWPMNTIM-VWLOTQADSA-N

物化性质

• 熔点：
  > 177° C (dec.)
• 沸点：
  688.6±65.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO（轻微、超声处理）、乙醇（轻微、加热、超声处理）

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  38
• 可旋转键数：
  26
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  144
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

Brincidofovir 是 [cidofovir] 的前药，因此它必须经历一些基本的代谢反应才能具有药理活性。进入目标细胞后，brincidofovir 的磷酸二酯键被水解以生成 cidofovir，然后 cidofovir 被磷酸化以生成活性物质：cidofovir 二磷酸盐。负责这一反应的具体酶尚未被阐明，但体外研究发现鞘磷脂磷酸二酯酶在 brincidofovir 的初始水解中发挥主要作用。Brincidofovir 有两个主要的无活性代谢物，CMX103 和 CMX064，它们是通过末端的碳进行羧化反应，然后经过几个周期的 CYP 介导的氧化反应和脂肪酸氧化生成的。这些反应至少部分由 CYP4F2 介导。

Brincidofovir is a pro-drug of [cidofovir] and as such must undergo some basic metabolic reactions to become pharmacologically active. Upon entering the target cell, the phosphodiester bond of brincidofovir is hydrolyzed to generate cidofovir, which is then phosphorylated to generate the active agent: cidofovir diphosphate. The specific enzyme(s) responsible for this reaction have not been elucidated, but _in vitro_ findings suggest sphingomyelin phosphodiesterase plays a major role in the initial hydrolysis of brincidofovir. There are two major inactive metabolites of brincidofovir, CMX103 and CMX064, which are generated via carboxylation of the terminal carbon followed by several cycles of CYP-mediated oxidative reactions and fatty acid oxidation. These reactions are mediated, at least in part, by CYP4F2.

来源:DrugBank

毒理性

• 肝毒性

在造血干细胞移植（HSCT）后成人及儿童预防巨细胞病毒和腺病毒感染的布林西多弗vir预注册临床试验中，与安慰剂（16%）治疗相比，布林西多弗vir（22%）的血清转氨酶升高更常见，HSCT后肝酶升高率通常较高。ALT升高超过正常上限5倍的情况出现在1.8%，而安慰剂组为1.4%，在接受布林西多弗vir的269名患者中有1人因ALT升高超过10倍ULN而停止治疗。ALT和AST升高出现在布林西多弗vir仅给药2或3次时，即治疗第1天和第8天，在某些试验中还包括第21天。在同一试验中，服用布林西多弗vir的患者中有6.5%出现轻度至中度血清胆红素升高，而安慰剂组为5.9%，这再次反映了HSCT后患者胆红素升高的高发生率。在健康人类志愿者的小型研究中，未观察到肝功能测试异常。自从布林西多弗vir获得批准以来，没有出现适合使用该药物的天花感染实例。然而，在其批准后不久出现的猴痘感染导致了对这一非批准适应症的使用。在接受布林西多弗vir治疗的猴痘病毒感染对象中，转氨酶升高很常见，但通常是无症状的、短暂的，并且没有胆红素升高或并发症状。因此，布林西多弗vir的使用经验有限。尽管有报道称使用布林西多弗vir会导致短暂的血清转氨酶升高，但尚未有与布林西多弗vir治疗相关的临床上明显的肝损伤的报告。

In preregistration clinical trials of brincidofovir as prevention of cytomegalovirus and adenovirus infection in adults and children after hematopoietic stem cell transplantation (HSCT), serum aminotransferase elevations were more frequent with brincidofovir (22%) than placebo (16%) treatment, the usual rate of hepatic enzyme elevations being high after HSCT. ALT elevations above 5 times the upper limit of normal (ULN) arose in 1.8% vs 1.4% , and one of 269 brincidofovir recipients discontinued therapy because of ALT elevations above 10 times ULN. The ALT and AST elevations arose early as brincidofovir was given only 2 or 3 times, on days 1 and 8 and in some trials day 21 of treatment. In the same trials mild-to-moderate elevations in serum bilirubin arose in 6.5% of those on brincidofovir vs 5.9% of placebo recipients, again reflecting the high rate of bilirubin elevations in patients after HSCT. In small studies in healthy human volunteers abnormalities of liver tests were not observed. Since approval of brincidofovir, there have been no instances of smallpox infection that qualified for its use. However, the emergence of mpox infection shortly after its approval has led to its use for this non-approved indication. Aminotransferase elevations were frequent in the mpox virus infected subjects treated with brincidofovir but were invariably asymptomatic, transient and without symptoms or concurrent bilirubin elevations. Thus, the total clinical experience with use of brincidofovir is limited. While transient serum aminotransferase elevations have been reported with its use, there have been no reports of clinically apparent liver injury linked to brincidofovir therapy.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：目前没有关于在哺乳期间使用布瑞纳克斯韦（brincidofovir）的信息。建议患有天花的人不要哺乳，因为通过直接接触有可能将天花病毒传给婴儿。这个预防措施可能也适用于猴痘。如果没有伤口靠近乳房，并且采取了适当的手、乳房、吸奶器和任何其他用于给婴儿提供乳汁的设备的清洁措施，提供泵取的乳汁可能是可行的。在更多的安全数据出现之前，可能更倾向于使用其他药物。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对哺乳和乳汁的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the use of brincidofovir during breastfeeding. Individuals with smallpox are recommended not to breastfeed their infant because of the risk of passing variola virus to the infant through direct contact. This precaution probably applies to monkeypox, also. Providing pumped milk to the infant may be possible if no lesions are near the breast and adequate precautions are taken with respect to cleaning hands, breasts, breast pumps and any other apparatuses used to provide milk to the infant. Until more safety data become available, an alternate drug may be preferred. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

Brincidofovir 在血浆中 >99% 与蛋白结合，尽管尚未阐明具体结合的蛋白。

Brincidofovir is >99% protein-bound in plasma, although the specific protein(s) to which it binds have not been elucidated.

来源:DrugBank

吸收、分配和排泄

• 吸收

Brincidofovir片剂的口服生物利用度为13.4%，悬浮液制剂的生物利用度为16.8%。口服给药后，Brincidofovir的Cmax和AUCtau分别为480 ng/mL和3400 ng·hr/mL。活性代谢物cidofovir二磷酸的Cmax和AUCtau分别为9.7 pg/106细胞和1200 pg·hr/106细胞。Brincidofovir的最大血浆浓度（Tmax）在大约给药后3小时达到，而cidofovir二磷酸的最大血浆浓度在大约给药后47小时达到。

The oral bioavailability of brincidofovir is 13.4% in its tablet formulation and 16.8% in its suspension formulation. Following oral administration, the Cmax and AUCtau of brincidofovir were 480 ng/mL and 3400 ng·hr/mL, respectively. The Cmax and AUCtau of the active metabolite, cidofovir diphosphate, were 9.7 pg/106 cells and 1200 pg·hr/106 cells, respectively. Maximum plasma concentrations (Tmax) of brincidofovir are reached at approximately 3 hours post-administration, while maximal plasma concentrations for cidofovir diphosphate are reached at approximately 47 hours post-administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Brincidofovir 通过代谢物在尿液（约51%）和粪便（约40%）中排出。

Brincidofovir is eliminated as metabolites in both the urine (~51%) and feces (~40%).

来源:DrugBank

吸收、分配和排泄

• 分布容积

布林西多福韦的表观分布容积为1230升。

The apparent volume of distribution of brincidofovir is 1230 L.

来源:DrugBank

吸收、分配和排泄

• 清除

健康的成年患者布林西多福韦的表观清除率为44.1 L/h。

The apparent clearance of brincidofovir in healthy adult patients is 44.1 L/h.

来源:DrugBank

安全信息

• 储存条件：
  -20°C，密闭保存，并保持干燥。

制备方法与用途

CMX001（Brincidofovir；HDP-CDV）是一种具有口服活性的Cidofovir（CDV）的亲脂衍生物，在体内外对某些疱疹病毒、腺病毒和正痘病毒展现出比CDV更强的活性。

反应信息

• 作为反应物：
  描述：

  hexadecyloxypropyl-cidofovir 在 ammonium hydroxide 作用下， 以 异丙醇 为溶剂， 以96.7%的产率得到CMX001 monoammonium salt
  参考文献：
  名称：

  Phosphonate Ester Derivatives and Methods of Synthesis Thereof

  摘要：

  该披露描述了合成膦酸酯衍生物的方法。根据该披露的首选方法允许大规模制备高纯度的膦酸酯化合物。在一些实施例中，根据该披露的首选方法还允许在比以往用于制备这类化合物的方法更好的产率下制备膦酸酯衍生物，而无需使用色谱纯化方法。还披露了膦酸酯衍生物的形态形式。

  公开号：

  US20120058976A1
• 作为产物：
  描述：

  环-1-(3-羟基-2-膦酰基甲氧基丙基)胞嘧啶 在 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 hexadecyloxypropyl-cidofovir
  参考文献：
  名称：

  Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir Exhibit Multiple-Log Enhancement of Antiviral Activity against Cytomegalovirus and Herpesvirus Replication In Vitro

  摘要：

  摘要 巨细胞病毒（CMV）视网膜炎在艾滋病患者中的发病率正在下降，但在器官移植和骨髓移植患者中仍是一个严重的临床问题。使用更昔洛韦（GCV）或缬更昔洛韦进行预防可降低 CMV 的发病率，但可能会导致 UL97 或 UL54 基因突变的耐药病毒的出现。如果能有其他类型的口服疗法来治疗 CMV 病，将会非常有用。我们合成了环状西多福韦（cCDV）和西多福韦（CDV）的十六烷氧基丙基和十八烷氧基乙基衍生物，发现与未修饰的 CDV 和 cCDV 相比，这些新型类似物对 CMV 的抗病毒活性提高了 2.5 到 4 个对数值。针对实验室 CMV 株系和各种 CMV 临床分离株（包括 UL97 和 UL54 基因突变的 GCV 耐药株）的活性提高了多个对数值。初步细胞研究表明，新型类似物的细胞穿透力更强，这可能是抗病毒活性提高的部分原因。1- O -十六烷氧基丙基-CDV、1- O O -十八烷氧基乙基-CDV 及其相应的 cCDV 类似物值得进一步进行临床前评估，以治疗和预防人类 CMV 和单纯疱疹病毒感染。

  DOI：

  10.1128/aac.46.8.2381-2386.2002

文献信息

• Enhanced Inhibition of Orthopoxvirus Replication In Vitro by Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir
  作者：Earl R. Kern、Caroll Hartline、Emma Harden、Kathy Keith、Natalie Rodriguez、James R. Beadle、Karl Y. Hostetler

  DOI：10.1128/aac.46.4.991-995.2002

  日期：2002.4

  reported to have activity against orthopoxvirus replication in vitro and in animal models when administered parenterally or by aerosol. To obtain better oral activity, we synthesized a novel series of analogs of CDV and cCDV by esterification with two long-chain alkoxyalkanols, 3-hexadecyloxy-1-propanol (HDP-CDV; HDP-cCDV) or 3-octadecyloxy-1-ethanol (ODE-CDV; ODE-cCDV). Their activities were evaluated

  肠胃外给药时，核苷酸膦酸酯西多福韦（CDV）和环状西多福韦（cCDV）是有效的抗病毒化合物，但口服吸收不好。据报道，这些化合物在肠胃外或通过气雾剂给药时在体外和动物模型中均具有抗正痘病毒复制的活性。为了获得更好的口服活性，我们通过与两种长链烷氧基烷醇，3-十六烷氧基-1-丙醇（HDP-CDV; HDP-cCDV）或3-十八烷氧基-1-乙醇酯化合成了一系列新的CDV和cCDV类似物。 （ODE-CDV; ODE-cCDV）。使用斑块减少测定法评估了它们的活性，并与被牛痘病毒（VV）或牛痘病毒（CV）感染的人包皮成纤维细胞（HFF）细胞中的CDV和cCDV进行了比较。HFF细胞中针对CDV和cCDV的VV的50％有效浓度（EC（50）s）为46。2和50.6 microM，而HDP-CDV和HDP-cCDV分别为0.84和3.8 microM。ODE-CDV和ODE-cCDV的EC（50）分别为0
• PHOSPHONATE COMPOUNDS
  申请人：——

  公开号：US20040019232A1

  公开（公告）日：2004-01-29

  The present invention relates to phosphonate compounds, compositions containing them, processes for obtaining them, and their use for treating a variety of medical disorders, e.g., osteoporosis and other disorders of bone metabolism, cancer, viral infections, and the like.

  本发明涉及膦酸酯化合物、含有它们的组合物、获取它们的方法，以及它们用于治疗各种医学疾病，例如骨质疏松症和其他骨代谢紊乱、癌症、病毒感染等的用途。
• Morphic forms of hexadecyloxypropyl-phosphonate esters and methods of synthesis thereof
  申请人：Chimerix, Inc.

  公开号：US08962829B1

  公开（公告）日：2015-02-24

  The disclosure describes methods of synthesis of phosphonate ester compounds. The methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity and stability. Also disclosed are morphic forms of phosphonate ester compounds.

  该披露描述了合成膦酸酯化合物的方法。根据该披露的方法，可以实现高纯度和稳定性的大规模制备膦酸酯化合物。还披露了膦酸酯化合物的形态形式。
• [EN] PHOSPHONATE COMPOUNDS<br/>[FR] COMPOSES DE PHOSPHONATE
  申请人：UNIV CALIFORNIA SAN DIEGO

  公开号：WO2001039724A2

  公开（公告）日：2001-06-07

  The present invention relates to phosphonate compounds, compositions containing them, processes for obtaining them, and their use for treating a variety of medical disorders, e.g., osteoporosis and other disorders of bone metabolism, cancer, viral infections, and the like.

  本发明涉及膦酸酯化合物、包含其的组合物、制备它们的过程以及它们用于治疗各种医学紊乱，例如骨质疏松症和其他骨代谢紊乱、癌症、病毒感染等。
• Phosphonate ester derivatives and methods of synthesis thereof
  申请人：Ware Roy W.

  公开号：US08569321B2

  公开（公告）日：2013-10-29

  The disclosure describes methods of synthesis of phosphonate ester derivatives. Preferred methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity. In some embodiments, preferred methods according to the disclosure also allow for the preparation of phosphonate ester derivatives without the use of chromatographic purification methods and in better yield than previously used methods for preparing such compounds. Also disclosed are morphic forms of phosphonate ester derivatives.

  该披露描述了磷酸酯衍生物的合成方法。根据该披露，首选方法可允许大规模制备高纯度的磷酸酯化合物。在某些实施例中，根据该披露的首选方法还可允许制备磷酸酯衍生物，而无需使用色谱纯化方法，并且比以前用于制备此类化合物的方法产率更高。披露的还有磷酸酯衍生物的形态形式。