4-(4-(1H-indazol-3-yl)benzamido)butanoic acid | 1032262-48-8

• 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: 4-(4-(1H-indazol-3-yl)benzamido)butanoic acid
• 英文别名: 4-[[4-(1H-indazol-3-yl)benzoyl]amino]butanoic acid
• CAS: 1032262-48-8
• 化学式: C₁₈H₁₇N₃O₃
• 分子量: 323.351
• InChiKey: KOKJMSXPORVHQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  95.1
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-(1H-indazol-3-yl)benzamido)butanoic acid 、 4-氨基-TEMPO 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 以68%的产率得到N-(4-(1-oxo-2,2,6,6-tetramethylpyridin-4-ylamino)-4-oxobutyl)-4-(1H-indazol-3-yl)benzamide
  参考文献：
  名称：

  Development of Paramagnetic Probes for Molecular Recognition Studies in Protein Kinases

  摘要：

  We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.

  DOI：

  10.1021/jm800068w
• 作为产物：
  描述：

  3-碘吲唑 在 4-二甲氨基吡啶 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 水 、 sodium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 78.17h， 生成 4-(4-(1H-indazol-3-yl)benzamido)butanoic acid
  参考文献：
  名称：

  Design and Characterization of a Potent and Selective Dual ATP- and Substrate-Competitive Subnanomolar Bidentate c-Jun N-Terminal Kinase (JNK) Inhibitor

  摘要：

  c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC50 = 18 nM; K-i = 1.5 nM) and JNK/substrate association in a displacement assay (IC50 = 46 nM; K-i = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice.

  DOI：

  10.1021/jm200479c

文献信息

• Design and Characterization of a Potent and Selective Dual ATP- and Substrate-Competitive Subnanomolar Bidentate c-Jun N-Terminal Kinase (JNK) Inhibitor
  作者：John L. Stebbins、Surya K. De、Petra Pavlickova、Vida Chen、Thomas Machleidt、Li-Hsing Chen、Christian Kuntzen、Shinichi Kitada、Michael Karin、Maurizio Pellecchia

  DOI：10.1021/jm200479c

  日期：2011.9.22

  c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC50 = 18 nM; K-i = 1.5 nM) and JNK/substrate association in a displacement assay (IC50 = 46 nM; K-i = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice.
• Development of Paramagnetic Probes for Molecular Recognition Studies in Protein Kinases
  作者：Jesus Vazquez、Surya K. De、Li-Hsing Chen、Megan Riel-Mehan、Aras Emdadi、Jason Cellitti、John L. Stebbins、Michele F. Rega、Maurizio Pellecchia

  DOI：10.1021/jm800068w

  日期：2008.6.1

  We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.