phenyl (ethyloxy-L-ethyl-glutamyl) phosphorochloridate | 936335-20-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: phenyl (ethyloxy-L-ethyl-glutamyl) phosphorochloridate
• 英文别名: phenyl-(ethoxy-L-ethylaspartyl)phosphorochloridate；diethyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]pentanedioate
• CAS: 936335-20-5
• 化学式: C₁₅H₂₁ClNO₆P
• 分子量: 377.762
• InChiKey: KUYWFCRNAJRSLF-LNHXHEARSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  24
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  phenyl (ethyloxy-L-ethyl-glutamyl) phosphorochloridate 在 甲酸 、 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 21.25h， 生成 ethyl N-[{1-((2R,3S,4R,5R)-5-azido-tetrahydro-3,4-dihydroxy-5-(hydroxymethyl)-furan-2-yl)pyrimidine-2,4(1H,3H)-dione} (phenoxy)-phosphoryl]-L-ethylglutamate
  参考文献：
  名称：

  Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside

  摘要：

  We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.

  DOI：

  10.1021/jm0613370

文献信息

• Discovery of a 2′-fluoro-2′- C -methyl C -nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties
  作者：Thorsten A. Kirschberg、Sammy Metobo、Michael O. Clarke、Vangelis Aktoudianakis、Darius Babusis、Ona Barauskas、Gabriel Birkus、Thomas Butler、Daniel Byun、Gregory Chin、Edward Doerffler、Thomas E. Edwards、Martijn Fenaux、Rick Lee、Willard Lew、Michael R. Mish、Eisuke Murakami、Yeojin Park、Neil H. Squires、Neeraj Tirunagari、Ting Wang、Mark Whitcomb、Jie Xu、Huiling Yang、Hong Ye、Lijun Zhang、Todd C. Appleby、Joy Y. Feng、Adrian S. Ray、Aesop Cho、Choung U. Kim

  DOI：10.1016/j.bmcl.2017.02.037

  日期：2017.4

  A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacolcinetic properties including efficient liver delivery in animals. (C) 2017 Published by Elsevier Ltd.
• The application of phosphoramidate ProTide technology to the potent anti-HCV compound 4′-azidocytidine (R1479)
  作者：Christopher McGuigan、Mary Rose Kelleher、Plinio Perrone、Sinead Mulready、Giovanna Luoni、Felice Daverio、Sonal Rajyaguru、Sophie Le Pogam、Isabel Najera、Joseph A. Martin、Klaus Klumpp、David B. Smith

  DOI：10.1016/j.bmcl.2009.05.099

  日期：2009.8

  We report the design, synthesis and evaluation of a family of ca 50 phosphoramidate ProTides of the potent anti-HCV compound 4 '-azidocytidine (R1479), with variation on the ester, amino acid and aryl moiety of the ProTide. Sub-mu M inhibitors of HCV emerge. The compounds are all non-cytotoxic in the replicon assay. We herein report detailed SARs for each of the regions of the ProTide. (C) 2009 Elsevier Ltd. All rights reserved.