(Z)-4-(4-(4-chlorobenzyl)-1-(cyclohexylmethyl)piperidin-4-yl)-2-hydroxy-4-oxobut-2-enoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (Z)-4-(4-(4-chlorobenzyl)-1-(cyclohexylmethyl)piperidin-4-yl)-2-hydroxy-4-oxobut-2-enoic acid
• 英文别名: (Z)-4-[4-[(4-Chlorophenyl)methyl]-1-(Cyclohexylmethyl)piperidin-4-Yl]-2-Oxidanyl-4-Oxidanylidene-But-2-Enoic Acid；(Z)-4-[4-[(4-chlorophenyl)methyl]-1-(cyclohexylmethyl)piperidin-4-yl]-2-hydroxy-4-oxobut-2-enoic acid
• 化学式: C₂₃H₃₀ClNO₄
• 分子量: 419.949
• InChiKey: XWMHHMXKNMXGDP-ZHZULCJRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  77.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  tert-butyl 4-acetyl-4-(4-chlorobenzyl)piperidine-1-carboxylate 在 盐酸 、 sodium methylate 、 potassium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 96.41h， 生成 (Z)-4-(4-(4-chlorobenzyl)-1-(cyclohexylmethyl)piperidin-4-yl)-2-hydroxy-4-oxobut-2-enoic acid
  参考文献：
  名称：

  一种综合的生物学方法，可指导流感病毒PA核酸内切酶的金属螯合抑制剂的开发。

  摘要：

  流感病毒PA核酸内切酶可裂解带帽的细胞前mRNA，从而引发病毒mRNA的合成，是新型抗流感病毒治疗方法的有希望的靶标。该酶的催化中心位于PA（PA-Nter）的N端，含有两个（或可能一个或三个）Mg（2+）或Mn（2+）离子，这对于其催化功能至关重要。对PA抑制剂的研究引起了极大的兴趣，这些抑制剂经过优化设计，可以占据活性位点并螯合金属离子。我们在这里集中于一系列包含不同支架的β-二酮酸（DKA）和DKA生物立体异构化合物，并在用PA-Nter的酶法测定中确定了它们的构效关系，以建立三维药效团模型。此外，我们开发了一种基于分子信标（MB）的PA-Nter分析，使我们能够比较Mn（2+）和Mg（2+）的抑制作用，后者可能是生物学上相关的辅助因子。这种实时MB检测使我们能够测量PA-Nter的酶动力学或进行高通量筛选。发现几种DKA衍生物可强烈抑制PA-Nter，IC50值可与原型L-742,

  DOI：

  10.1124/mol.114.095588

文献信息

• FRAGMENTS OF THE PA SUBUNIT OF RNA DEPENDENT RNA POLYMERASE FROM PANDEMIC INFLUENZA VIRUS A 2009 H1N1, AND THEIR USE
  申请人：EUROPEAN MOLECULAR BIOLOGY LABORATORY (EMBL)

  公开号：EP2547696A2

  公开（公告）日：2013-01-23
• INFLUENZA A 2009 PANDEMIC H1N1 POLYPEPTIDE FRAGMENTS COMPRISING ENDONUCLEASE ACTIVITY AND THEIR USE
  申请人：Cusack Stephen

  公开号：US20130023565A1

  公开（公告）日：2013-01-24

  The present invention relates to polypeptide fragments comprising an amino-terminal fragment of the PA subunit of a viral RNA-dependent RNA polymerase possessing endonuclease activity, wherein said PA subunit is from Influenza A 2009 pan-demic H1N1 virus or is a variant thereof. This invention also relates to (i) crystals of the polypeptide fragments which are suitable for structure determination of said polypeptide fragments using X-ray crystallography and (ii) computational methods using the structural coordinates of said polypeptide to screen for and design compounds that modulate, preferably inhibit the endonucleolytically active site within the polypeptide fragment. In addition, this invention relates to methods identifying compounds that bind to the PA polypeptide fragments possessing endonuclease activity and preferably inhibit said endonucleolytic activity, preferably in a high throughput setting. This invention also relates to compounds which are able to modulate, preferably to inhibit, the endonuclease activity of the PA subunit polypeptide fragment or variant thereof of the present invention and pharmaceutical compositions comprising said compounds for the treatment of disease conditions caused by viral infections with viruses of the Orthomyxoviridae family, Bunyaviridae family and/or Arenviridae family, preferably caused by viral infections with Influenza A 2009 pandemic H1N1 virus. Preferably, said compounds are identifiable by the methods disclosed herein or said pharmaceutical compositions are producible by the methods disclosed herein.
• INFLUENZA A 2009 PANDEMIC H1N1 POLYPEPTIDE FRAGMENTS COMPRISING ENDONUCLEASE ACTIVITY AND THEIR USE
  申请人：Cusack Stephen

  公开号：US20160053241A1

  公开（公告）日：2016-02-25

  The present invention relates to polypeptide fragments comprising an amino-terminal fragment of the PA subunit of a viral RNA-dependent RNA polymerase possessing endonuclease activity, wherein said PA subunit is from Influenza A 2009 pandemic H1N1 virus or is a variant thereof. This invention also relates to (i) crystals of the polypeptide fragments which are suitable for structure determination of said polypeptide fragments using X-ray crystallography and (ii) computational methods using the structural coordinates of said polypeptide to screen for and design compounds that modulate, preferably inhibit the endonucleolytically active site within the polypeptide fragment. In addition, this invention relates to methods identifying compounds that bind to the PA polypeptide fragments possessing endonuclease activity and preferably inhibit said endonucleolytic activity, preferably in a high throughput setting. This invention also relates to compounds which are able to modulate, preferably to inhibit, the endonuclease activity of the PA subunit polypeptide fragment or variant thereof of the present invention and pharmaceutical compositions comprising said compounds for the treatment of disease conditions caused by viral infections with viruses of the Orthomyxoviridae family, Bunyaviridae family and/or Arenviridae family, preferably caused by viral infections with Influenza A 2009 pandemic H1N1 virus. Preferably, said compounds are identifiable by the methods disclosed herein or said pharmaceutical compositions are producible by the methods disclosed herein.
• US9181307B2
  申请人：——

  公开号：US9181307B2

  公开（公告）日：2015-11-10
• US9783794B2
  申请人：——

  公开号：US9783794B2

  公开（公告）日：2017-10-10