4-[2-[[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy]-2-oxo-1,3,2lambda5-dioxaphosphinan-4-yl]benzonitrile | 926654-19-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: 4-[2-[[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy]-2-oxo-1,3,2lambda5-dioxaphosphinan-4-yl]benzonitrile
• 英文别名: 4-[2-[[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy]-2-oxo-1,3,2λ5-dioxaphosphinan-4-yl]benzonitrile
• CAS: 926654-19-5
• 化学式: C₂₁H₂₃N₆O₇P
• 分子量: 502.423
• InChiKey: QMCZZZCOVMJSCF-ZGRMHGJHSA-N

物化性质

• 沸点：
  794.8±70.0 °C(Predicted)
• 密度：
  1.73±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  188
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  4-[2-[[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy]-2-oxo-1,3,2lambda5-dioxaphosphinan-4-yl]benzonitrile 、 N,N'-羰基二咪唑 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Liver-Targeted Prodrugs of 2‘-C-Methyladenosine for Therapy of Hepatitis C Virus Infection

  摘要：

  2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.

  DOI：

  10.1021/jm0701021
• 作为产物：
  描述：

  2’-C-甲基腺苷 在 叔丁基氯化镁 、 对甲苯磺酸 、 三氟乙酸 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 4-[2-[[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy]-2-oxo-1,3,2lambda5-dioxaphosphinan-4-yl]benzonitrile
  参考文献：
  名称：

  Liver-Targeted Prodrugs of 2‘-C-Methyladenosine for Therapy of Hepatitis C Virus Infection

  摘要：

  2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.

  DOI：

  10.1021/jm0701021

文献信息

• Novel 2'-c-methyl and 4'c-methyl nucleoside derivatives
  申请人：Erion Mark D.

  公开号：US20090118223A1

  公开（公告）日：2009-05-07

  Novel 2′-C-methyl nucleoside 5′-monophosphate and 4′-C-methyl nucleoside 5′-monophosphate derivatives, stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof, their preparation, and their uses for the treatment of hepatitis C viral infection are described.
• Liver-Targeted Prodrugs of 2‘-<i>C</i>-Methyladenosine for Therapy of Hepatitis C Virus Infection
  作者：Scott J. Hecker、K. Raja Reddy、Paul D. van Poelje、Zhili Sun、Wenjian Huang、Vaibhav Varkhedkar、M. Venkat Reddy、James M. Fujitaki、David B. Olsen、Kenneth A. Koeplinger、Serge H. Boyer、David L. Linemeyer、Malcolm MacCoss、Mark D. Erion

  DOI：10.1021/jm0701021

  日期：2007.8.1

  2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.