4,4'-(((3R,5R)-1-(but-3-yn-1-yloxy)-7-((1S,2S,6R,8S,8aR)-8-((2,2-dimethylbutanoyl)oxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-1-oxoheptane-3,5-diyl)bis(oxy))bis(4-oxobutanoic acid) | 1572927-17-3

• 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: 4,4'-(((3R,5R)-1-(but-3-yn-1-yloxy)-7-((1S,2S,6R,8S,8aR)-8-((2,2-dimethylbutanoyl)oxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-1-oxoheptane-3,5-diyl)bis(oxy))bis(4-oxobutanoic acid)
• CAS: 1572927-17-3
• 化学式: C₃₇H₅₂O₁₂
• 分子量: 688.813
• InChiKey: VMKFMKGBYLSLMV-RZWZJFIRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.42
• 重原子数：
  49.0
• 可旋转键数：
  20.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  179.8
• 氢给体数：
  2.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  4,4'-(((3R,5R)-1-(but-3-yn-1-yloxy)-7-((1S,2S,6R,8S,8aR)-8-((2,2-dimethylbutanoyl)oxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-1-oxoheptane-3,5-diyl)bis(oxy))bis(4-oxobutanoic acid) 、 辛伐他汀 在 N,N'-二环己基碳二亚胺 、 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 1.58h， 以58.6%的产率得到
  参考文献：
  名称：

  [EN] MACROMOLECULAR PRODRUGS FOR HARD TISSUE AND METHODS OF USE THEREOF
  [FR] PROMÉDICAMENTS MACROMOLÉCULAIRES POUR TISSU DUR ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  提供用于静脉给药的组成物以及包括疏水性骨骼合成剂的巨分子前药治疗骨骼疾病、紊乱和骨折的方法。具体而言，提供新颖的巨分子两亲性前药，其中至少三分子辛伐他汀与聚乙二醇共轭，它们在水溶液中自发形成胶束。

  公开号：

  WO2014036548A1
• 作为产物：
  描述：

  丁二酸酐 、 (3R,5R)-but-3-yn-1-yl 7-((1S,2S,6R,8S,8aR)-8-((2,2-dimethylbutanoyl)oxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-3,5-dihydroxyheptanoate 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 以94.6%的产率得到4,4'-(((3R,5R)-1-(but-3-yn-1-yloxy)-7-((1S,2S,6R,8S,8aR)-8-((2,2-dimethylbutanoyl)oxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-1-oxoheptane-3,5-diyl)bis(oxy))bis(4-oxobutanoic acid)
  参考文献：
  名称：

  [EN] MACROMOLECULAR PRODRUGS FOR HARD TISSUE AND METHODS OF USE THEREOF
  [FR] PROMÉDICAMENTS MACROMOLÉCULAIRES POUR TISSU DUR ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  提供用于静脉给药的组成物以及包括疏水性骨骼合成剂的巨分子前药治疗骨骼疾病、紊乱和骨折的方法。具体而言，提供新颖的巨分子两亲性前药，其中至少三分子辛伐他汀与聚乙二醇共轭，它们在水溶液中自发形成胶束。

  公开号：

  WO2014036548A1

文献信息

• Simvastatin prodrug micelles target fracture and improve healing
  作者：Zhenshan Jia、Yijia Zhang、Yen Hsun Chen、Anand Dusad、Hongjiang Yuan、Ke Ren、Fei Li、Edward V. Fehringer、P. Edward Purdue、Steven R. Goldring、Aaron Daluiski、Dong Wang

  DOI：10.1016/j.jconrel.2014.12.028

  日期：2015.2

  Simvastatin (SIM), a widely used anti-lipidemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug's hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles' therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing. (C) 2014 Elsevier B.V. All rights reserved.