ethyl (2S)-2-[[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-phenoxyphosphoryl]oxypropanoate | 1234081-02-7

• 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 (2S)-2-[[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-phenoxyphosphoryl]oxypropanoate
• CAS: 1234081-02-7
• 化学式: C₂₁H₂₃FN₅O₇P
• 分子量: 507.415
• InChiKey: KLHQUMPQNXSFLX-VVLAXKTRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  150
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  L(-)-乳酸乙酯 、 phenyl [5-(R)-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-(R)-yloxymethyl]phosphonic acid 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以19%的产率得到ethyl (2S)-2-[[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-phenoxyphosphoryl]oxypropanoate
  参考文献：
  名称：

  Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2010.03.041

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.