(2R,3R,4R,5R,6R)-methyl 5-acetamido-4-amino-2,3-difluoro-6-((1R,2R)-1,2,3-trihydroxypropyl)tetrahydro-2H-pyran-2-carboxylate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2R,3R,4R,5R,6R)-methyl 5-acetamido-4-amino-2,3-difluoro-6-((1R,2R)-1,2,3-trihydroxypropyl)tetrahydro-2H-pyran-2-carboxylate
• 英文别名: 4-amino-2,3-difluorosialic acid methyl ester；methyl (2R,3R,4R,5R,6R)-5-acetamido-4-amino-2,3-difluoro-6-[(1R,2R)-1,2,3-trihydroxypropyl]oxane-2-carboxylate
• 化学式: C₁₂H₂₀F₂N₂O₇
• 分子量: 342.297
• InChiKey: CFKADAYOSOOANH-WYNIBRNHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  151
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (2R,3R,4R,5R,6R)-methyl 5-acetamido-4-amino-2,3-difluoro-6-((1R,2R)-1,2,3-trihydroxypropyl)tetrahydro-2H-pyran-2-carboxylate 在 水 、 sodium hydroxide 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 3.0h， 生成 4-ureido-2,3-difluorosialic acid sodium salt
  参考文献：
  名称：

  了解取代的二氟唾液酸对病毒神经氨酸酶的抑制作用。

  摘要：

  二氟唾液酸（DFSA）对流感神经氨酸酶的基于机制的抑制不仅通过引入4-氨基或4-胍取代基变得高度特异性，而且可大大延长重新活化的半衰期。令人惊奇的是，测量一系列此类取代的DFSA的自发水解的速率常数，令人惊讶地发现，固有的诱导作用在速率降低中起着很小的作用，与酶的相互作用更为重要。

  DOI：

  10.1039/c4cc08256g
• 作为产物：
  描述：

  在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 生成 (2R,3R,4R,5R,6R)-methyl 5-acetamido-4-amino-2,3-difluoro-6-((1R,2R)-1,2,3-trihydroxypropyl)tetrahydro-2H-pyran-2-carboxylate
  参考文献：
  名称：

  Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay

  摘要：

  Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.04.059

文献信息

• Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay
  作者：Steve Arns、Jason Tan、Sharon Sun、Adam Galey、Natalia Zisman、Fiona Ross、Jenna Udechukwu、Samantha Dercho、Vionarica Gusti、Jay Paquette、Murray Webb、Elyse Bourque、Stephen G. Withers、Richard Liggins

  DOI：10.1016/j.bmcl.2015.04.059

  日期：2015.6

  Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs. (C) 2015 Elsevier Ltd. All rights reserved.
• Understanding viral neuraminidase inhibition by substituted difluorosialic acids
  作者：S. Weck、K. Robinson、M. R. Smith、S. G. Withers

  DOI：10.1039/c4cc08256g

  日期：——

  Mechanism-based inhibition of influenza neuraminidases by difluorosialic acids (DFSA) is not only rendered highly specific by incorporation of 4-amino or 4-guanidine substituents but also the half-life for reactivation is greatly increased. Measurement of rate constants for spontaneous hydrolysis of a series of such substituted DFSAs reveals, surprisingly, that inherent inductive effects play very

  二氟唾液酸（DFSA）对流感神经氨酸酶的基于机制的抑制不仅通过引入4-氨基或4-胍取代基变得高度特异性，而且可大大延长重新活化的半衰期。令人惊奇的是，测量一系列此类取代的DFSA的自发水解的速率常数，令人惊讶地发现，固有的诱导作用在速率降低中起着很小的作用，与酶的相互作用更为重要。