9-(R)-[5-[(R)-bis-(isopropyloxycarbonyloxymethyl)phosphonyl]methoxy-3-fluoro-2,5-dihydrofuran-2-yl]-9H-adenine | 1234080-95-5

• 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: 9-(R)-[5-[(R)-bis-(isopropyloxycarbonyloxymethyl)phosphonyl]methoxy-3-fluoro-2,5-dihydrofuran-2-yl]-9H-adenine
• 英文别名: [[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-(isopropoxycarbonyloxymethoxy)phosphoryl]oxymethyl isopropyl carbonate；[[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate
• CAS: 1234080-95-5
• 化学式: C₂₀H₂₇FN₅O₁₁P
• 分子量: 563.433
• InChiKey: RUECDIURZZLAAQ-KBXCAEBGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  38
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  195
• 氢给体数：
  1
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  [5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]phosphonic acid disodium salt 、 氯甲基碳酸异丙酯 在 三乙胺 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 3.0h， 以7%的产率得到9-(R)-[5-[(R)-bis-(isopropyloxycarbonyloxymethyl)phosphonyl]methoxy-3-fluoro-2,5-dihydrofuran-2-yl]-9H-adenine
  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.