diphenyl [5-(R)-(6-methoxypurin-9-yl)-4-(R)-fluoro-3-(R)-iodo-tetrahydrofuran-2(R)-yloxymethyl]phosphonic acid | 1234080-98-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: diphenyl [5-(R)-(6-methoxypurin-9-yl)-4-(R)-fluoro-3-(R)-iodo-tetrahydrofuran-2(R)-yloxymethyl]phosphonic acid
• CAS: 1234080-98-8
• 化学式: C₂₃H₂₁FIN₄O₆P
• 分子量: 626.32
• InChiKey: IFNUEXOYZCQCIF-JRSMBCBASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.16
• 重原子数：
  36.0
• 可旋转键数：
  9.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  106.82
• 氢给体数：
  0.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  diphenyl [5-(R)-(6-methoxypurin-9-yl)-4-(R)-fluoro-3-(R)-iodo-tetrahydrofuran-2(R)-yloxymethyl]phosphonic acid 在 吡啶 、 N-甲基咪唑 、 ammonium hydroxide 、 sodium hypochlorite 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 溶剂黄146 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 6.5h， 生成 ethyl (2S)-2-[[[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-phenoxy-phosphoryl]amino]propanoate
  参考文献：
  名称：

  CYCLOPENTENE-OXYMETHYLENE PHOSPHONAMIDATES AND RELATED COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS

  摘要：

  Substituted cyclopentene-oxymethylene phosphonamidates and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV- K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein.

  公开号：

  WO2024107859A1
• 作为产物：
  描述：

  ((2R,3R,4S,5R)-3-(benzoyloxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methyl benzoate 在 Jones reagent 、 偶氮二甲酸二异丙酯 、 silica gel 、 一溴化碘 、 potassium carbonate 、 三苯基膦 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 18.0h， 生成 diphenyl [5-(R)-(6-methoxypurin-9-yl)-4-(R)-fluoro-3-(R)-iodo-tetrahydrofuran-2(R)-yloxymethyl]phosphonic acid
  参考文献：
  名称：

  CYCLOPENTENE-OXYMETHYLENE PHOSPHONAMIDATES AND RELATED COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS

  摘要：

  Substituted cyclopentene-oxymethylene phosphonamidates and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV- K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein.

  公开号：

  WO2024107859A1

文献信息

• Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
  作者：Richard L. Mackman、Adrian S. Ray、Hon C. Hui、Lijun Zhang、Gabriel Birkus、Constantine G. Boojamra、Manoj C. Desai、Janet L. Douglas、Ying Gao、Deborah Grant、Genevieve Laflamme、Kuei-Ying Lin、David Y. Markevitch、Ruchika Mishra、Martin McDermott、Rowchanak Pakdaman、Oleg V. Petrakovsky、Jennifer E. Vela、Tomas Cihlar

  DOI：10.1016/j.bmc.2010.03.041

  日期：2010.5

  GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metabolite 15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3 mg/kg) in Beagle dogs, high levels (>9.0 mu M) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate. (C) 2010 Elsevier Ltd. All rights reserved.