2-[2-(2-Methoxyethoxymethoxy)-3-phenylphenyl]-1-benzofuran-5-carboximidamide | 1026799-01-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 2-芳基苯并呋喃类黄酮
• 英文名称: 2-[2-(2-Methoxyethoxymethoxy)-3-phenylphenyl]-1-benzofuran-5-carboximidamide
• CAS: 1026799-01-8
• 化学式: C₂₅H₂₄N₂O₄
• 分子量: 416.477
• InChiKey: AYKBRBZAZKHOSP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  90.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[2-(2-Methoxyethoxymethoxy)-3-phenylphenyl]-1-benzofuran-5-carboximidamide 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 2-(2-Hydroxy-biphenyl-3-yl)-benzofuran-5-carboxamidine
  参考文献：
  名称：

  Development of Serine Protease Inhibitors Displaying a Multicentered Short (<2.3 Å) Hydrogen Bond Binding Mode:  Inhibitors of Urokinase-Type Plasminogen Activator and Factor Xa

  摘要：

  Novel scaffolds that bind to serine proteases through a unique network of short hydrogen bonds to the catalytic Ser195 have been developed. The resulting potent serine protease inhibitors were designed from lead molecule 2-(2-hydroxyphenyl)1H-benzoimidazole-5-carboxamidine, 6b, which is known to display several modes of binding. For instance, 6b can recruit zinc and bind in a manner similar to that reported by bis(5-amidino-2-benzimidazolyl)methane (BABIM) (Nature 1998, 391, 608-612).(1) Alternatively, 6b can bind in the absence of zinc through a multicentered network of short (<2.3 Angstrom) hydrogen bonds. The lead structure was optimized in the zinc-independent binding mode toward a panel of six human serine proteases to yield optimized inhibitors such as 2-(3-bromo-2-hydroxy-5-methylphenyl)-1H-indole-5-carboxamidine, 22a, and 2-(2-hydroxybiphenyl-3-yl)-1H-indole-5-carboxamidine, 22f. Structure-activity relationships determined that, apart from the amidine function, an indole or benzimidazole and an ortho substituted phenol group were also essential components for optimal potency. The affinities (K-i) of 22a and 22f, for example, bearing these groups ranged from 8 to 600 nM toward a panel of six human serine proteases. High-resolution crystal structures revealed that the binding mode of these molecules in several of the enzymes was identical to that of 6b and involved short (<2.3 Angstrom) hydrogen bonds among the inhibitor hydroxyl oxygen, Ser195, and a water molecule trapped in the oxyanion hole. In summation, novel and potent trypsin-like serine protease inhibitors possessing a unique mode of binding have been discovered.

  DOI：

  10.1021/jm0100638
• 作为产物：
  描述：

  4-羟基-3-碘苯甲腈 在 10percent Pd/C bis-triphenylphosphine-palladium(II) chloride 、 氢气 、 羟胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 2-[2-(2-Methoxyethoxymethoxy)-3-phenylphenyl]-1-benzofuran-5-carboximidamide
  参考文献：
  名称：

  Development of Serine Protease Inhibitors Displaying a Multicentered Short (<2.3 Å) Hydrogen Bond Binding Mode:  Inhibitors of Urokinase-Type Plasminogen Activator and Factor Xa

  摘要：

  Novel scaffolds that bind to serine proteases through a unique network of short hydrogen bonds to the catalytic Ser195 have been developed. The resulting potent serine protease inhibitors were designed from lead molecule 2-(2-hydroxyphenyl)1H-benzoimidazole-5-carboxamidine, 6b, which is known to display several modes of binding. For instance, 6b can recruit zinc and bind in a manner similar to that reported by bis(5-amidino-2-benzimidazolyl)methane (BABIM) (Nature 1998, 391, 608-612).(1) Alternatively, 6b can bind in the absence of zinc through a multicentered network of short (<2.3 Angstrom) hydrogen bonds. The lead structure was optimized in the zinc-independent binding mode toward a panel of six human serine proteases to yield optimized inhibitors such as 2-(3-bromo-2-hydroxy-5-methylphenyl)-1H-indole-5-carboxamidine, 22a, and 2-(2-hydroxybiphenyl-3-yl)-1H-indole-5-carboxamidine, 22f. Structure-activity relationships determined that, apart from the amidine function, an indole or benzimidazole and an ortho substituted phenol group were also essential components for optimal potency. The affinities (K-i) of 22a and 22f, for example, bearing these groups ranged from 8 to 600 nM toward a panel of six human serine proteases. High-resolution crystal structures revealed that the binding mode of these molecules in several of the enzymes was identical to that of 6b and involved short (<2.3 Angstrom) hydrogen bonds among the inhibitor hydroxyl oxygen, Ser195, and a water molecule trapped in the oxyanion hole. In summation, novel and potent trypsin-like serine protease inhibitors possessing a unique mode of binding have been discovered.

  DOI：

  10.1021/jm0100638

文献信息

• Development of Serine Protease Inhibitors Displaying a Multicentered Short (&lt;2.3 Å) Hydrogen Bond Binding Mode:  Inhibitors of Urokinase-Type Plasminogen Activator and Factor Xa
  作者：Erik Verner、Bradley A. Katz、Jeffrey R. Spencer、Darin Allen、Jason Hataye、Witold Hruzewicz、Hon C. Hui、Aleksandr Kolesnikov、Yong Li、Christine Luong、Arnold Martelli、Kesavan Radika、Roopa Rai、Miles She、William Shrader、Paul A. Sprengeler、Sean Trapp、Jing Wang、Wendy B. Young、Richard L. Mackman

  DOI：10.1021/jm0100638

  日期：2001.8.1

  Novel scaffolds that bind to serine proteases through a unique network of short hydrogen bonds to the catalytic Ser195 have been developed. The resulting potent serine protease inhibitors were designed from lead molecule 2-(2-hydroxyphenyl)1H-benzoimidazole-5-carboxamidine, 6b, which is known to display several modes of binding. For instance, 6b can recruit zinc and bind in a manner similar to that reported by bis(5-amidino-2-benzimidazolyl)methane (BABIM) (Nature 1998, 391, 608-612).(1) Alternatively, 6b can bind in the absence of zinc through a multicentered network of short (<2.3 Angstrom) hydrogen bonds. The lead structure was optimized in the zinc-independent binding mode toward a panel of six human serine proteases to yield optimized inhibitors such as 2-(3-bromo-2-hydroxy-5-methylphenyl)-1H-indole-5-carboxamidine, 22a, and 2-(2-hydroxybiphenyl-3-yl)-1H-indole-5-carboxamidine, 22f. Structure-activity relationships determined that, apart from the amidine function, an indole or benzimidazole and an ortho substituted phenol group were also essential components for optimal potency. The affinities (K-i) of 22a and 22f, for example, bearing these groups ranged from 8 to 600 nM toward a panel of six human serine proteases. High-resolution crystal structures revealed that the binding mode of these molecules in several of the enzymes was identical to that of 6b and involved short (<2.3 Angstrom) hydrogen bonds among the inhibitor hydroxyl oxygen, Ser195, and a water molecule trapped in the oxyanion hole. In summation, novel and potent trypsin-like serine protease inhibitors possessing a unique mode of binding have been discovered.