cis-5'-O-[4-(5-methyl-pyridin-3-yl)-2-oxo-1,3,2-dioxaphosphorin-2-yl]-2'-C-methyladenosine | 926654-45-7

• 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: cis-5'-O-[4-(5-methyl-pyridin-3-yl)-2-oxo-1,3,2-dioxaphosphorin-2-yl]-2'-C-methyladenosine
• 英文别名: (2R,3R,4R,5R)-2-(6-aminopurin-9-yl)-3-methyl-5-[[4-(5-methylpyridin-3-yl)-2-oxo-1,3,2lambda5-dioxaphosphinan-2-yl]oxymethyl]oxolane-3,4-diol；(2R,3R,4R,5R)-2-(6-aminopurin-9-yl)-3-methyl-5-[[4-(5-methylpyridin-3-yl)-2-oxo-1,3,2λ5-dioxaphosphinan-2-yl]oxymethyl]oxolane-3,4-diol
• CAS: 926654-45-7
• 化学式: C₂₀H₂₅N₆O₇P
• 分子量: 492.428
• InChiKey: FYTFKQYWUIUZAJ-GJDHVLDNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  177
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 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 cis-5'-O-[4-(5-methyl-pyridin-3-yl)-2-oxo-1,3,2-dioxaphosphorin-2-yl]-2'-C-methyladenosine
  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.