ethyl hydrogen ((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate | 1234080-92-2

• 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: ethyl hydrogen ((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate
• 英文别名: [(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-ethoxyphosphinic acid
• CAS: 1234080-92-2
• 化学式: C₁₂H₁₅FN₅O₅P
• 分子量: 359.254
• InChiKey: JIWHCAKAHOSGRS-QPUJVOFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.31
• 重原子数：
  24.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  134.61
• 氢给体数：
  2.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  ethyl hydrogen ((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate 在 2,6-二甲基吡啶 、 三甲基溴硅烷 作用下， 以 二甲基亚砜 、 乙腈 为溶剂， 反应 18.75h， 生成 ((((2R,5R)-5-(6-Amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(piperidin-1-yl)phosphinic acid
  参考文献：
  名称：

  [EN] METHODS OF TREATING MEDICAL CONDITIONS AND INHIBITING LINE1 REVERSE TRANSCRIPTASE USING A SUBSTITUTED 4-FLUORO-2,5-DIHYDROFURANYL PHOSPHONIC ACID OR RELATED COMPOUND
  [FR] MÉTHODES DE TRAITEMENT D'ÉTATS MÉDICAUX ET D'INHIBITION DE LA TRANSCRIPTASE INVERSE DE LA LINE1 À L'AIDE D'UN ACIDE 4-FLUORO-2,5-DIHYDROFURANYLE PHOSPHONIQUE SUBSTITUÉ OU D'UN COMPOSÉ APPARENTÉ

  摘要：

  The invention provides methods and compositions for treating medical disorders, such as cancer, and inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase using a substituted 4-fluoro-2,5-dihydrofuranyl phosphonic acid or related compound.

  公开号：

  WO2022245814A1
• 作为产物：
  描述：

  diethyl ((((2R,5R)-4-fluoro-5-(6-methoxy-9H-purin-9-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate 在 ammonium hydroxide 作用下， 以 乙醇 为溶剂， 以38 %的产率得到ethyl hydrogen ((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate
  参考文献：
  名称：

  [EN] METHODS OF TREATING MEDICAL CONDITIONS AND INHIBITING LINE1 REVERSE TRANSCRIPTASE USING A SUBSTITUTED 4-FLUORO-2,5-DIHYDROFURANYL PHOSPHONIC ACID OR RELATED COMPOUND
  [FR] MÉTHODES DE TRAITEMENT D'ÉTATS MÉDICAUX ET D'INHIBITION DE LA TRANSCRIPTASE INVERSE DE LA LINE1 À L'AIDE D'UN ACIDE 4-FLUORO-2,5-DIHYDROFURANYLE PHOSPHONIQUE SUBSTITUÉ OU D'UN COMPOSÉ APPARENTÉ

  摘要：

  The invention provides methods and compositions for treating medical disorders, such as cancer, and inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase using a substituted 4-fluoro-2,5-dihydrofuranyl phosphonic acid or related compound.

  公开号：

  WO2022245814A1

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.