(2R,3R,4S,5S)-2-Hydroxymethyl-5-(3-phenyl-4-phenylamino-pyrazolo[3,4-d]pyrimidin-1-yl)-tetrahydro-furan-3,4-diol | 164514-25-4

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 吡唑并[3，4-d]嘧啶糖苷
• 英文名称: (2R,3R,4S,5S)-2-Hydroxymethyl-5-(3-phenyl-4-phenylamino-pyrazolo[3,4-d]pyrimidin-1-yl)-tetrahydro-furan-3,4-diol
• 英文别名: (2R,3R,4S,5S)-2-(4-anilino-3-phenylpyrazolo[3,4-d]pyrimidin-1-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 164514-25-4
• 化学式: C₂₂H₂₁N₅O₄
• 分子量: 419.44
• InChiKey: BBPPPQFKQHQFSL-DJZBOODTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  126
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,3R,4S,5S)-2-Hydroxymethyl-5-(3-phenyl-4-phenylamino-pyrazolo[3,4-d]pyrimidin-1-yl)-tetrahydro-furan-3,4-diol 在 盐酸 、 氨 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 丙酮 为溶剂， 反应 96.25h， 生成 4-N-phenylamino-3-phenyl-1-(5-amino-5-deoxy-2,3-O-isopropylidene-α-L-lyxofuranosyl)pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  Adenosine Kinase Inhibitors. 3. Synthesis, SAR, and Antiinflammatory Activity of a Series of l-Lyxofuranosyl Nucleosides

  摘要：

  Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, L-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical. orientation of the CH2OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-L-lyxofuranosyl. nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC50 = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propylxanthine (DMPX) is also described.

  DOI：

  10.1021/jm030230z
• 作为产物：
  描述：

  methyl L-lyxofuranoside 在 4-二甲氨基吡啶 、 硝基甲烷 、 硫酸 、 三氟化硼乙醚 、 sodium methylate 、 溶剂黄146 作用下， 以 吡啶 、 甲醇 为溶剂， 反应 34.0h， 生成 (2R,3R,4S,5S)-2-Hydroxymethyl-5-(3-phenyl-4-phenylamino-pyrazolo[3,4-d]pyrimidin-1-yl)-tetrahydro-furan-3,4-diol
  参考文献：
  名称：

  Adenosine Kinase Inhibitors. 3. Synthesis, SAR, and Antiinflammatory Activity of a Series of l-Lyxofuranosyl Nucleosides

  摘要：

  Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, L-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical. orientation of the CH2OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-L-lyxofuranosyl. nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC50 = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propylxanthine (DMPX) is also described.

  DOI：

  10.1021/jm030230z

文献信息

• ADENOSINE KINASE INHIBITORS COMPRISING LYXOFURANOSYL DERIVATIVES
  申请人：GENSIA, INC.

  公开号：EP0684953A1

  公开（公告）日：1995-12-06
• EP0684953A4
  申请人：——

  公开号：EP0684953A4

  公开（公告）日：1999-12-22
• [EN] ADENOSINE KINASE INHIBITORS COMPRISING LYXOFURANOSYL DERIVATIVES<br/>[FR] INHIBITEURS D'ADENOSINE-KINASE COMPRENANT DES DERIVES DE LYXOFURANOSYLE
  申请人：GENSIA, INC.

  公开号：WO1994018215A1

  公开（公告）日：1994-08-18

  (EN) Novel lyxose derivatives which selectively inhibit adenosine kinase and methods of preparing these compounds are provided. These compounds are useful in treating certain conditions in vivo which may be ameliorated by increased local concentrations of adenosine. The figure depicts levels of acadesine and ZMP in heart tissue after intravenous administration of compound 'A' of the instant invention.(FR) Nouveaux dérivés de lyxose inhibant sélectivement l'adénosine-kinase, et procédés de préparation de ces composés. Ceux-ci peuvent être utilisés pour le traitement in vivo de certains états pouvant être soignés par des concentrations locales accrues d'adénosine. La figure illustre les niveaux d'acadésine et de ZMP dans les tissus cardiaques après l'administration intraveineuse du composé 'A' de la présente invention.
• Adenosine Kinase Inhibitors. 3. Synthesis, SAR, and Antiinflammatory Activity of a Series of <scp>l</scp>-Lyxofuranosyl Nucleosides
  作者：Bheemarao G. Ugarkar、Angelo J. Castellino、Jay S. DaRe、Michele Ramirez-Weinhouse、Joseph J. Kopcho、Sanna Rosengren、Mark D. Erion

  DOI：10.1021/jm030230z

  日期：2003.10.1

  Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, L-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical. orientation of the CH2OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-L-lyxofuranosyl. nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC50 = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propylxanthine (DMPX) is also described.