methyl 4-(4-(1H-indazol-3-yl)benzamido)butanoate | 1032262-46-6

• 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: methyl 4-(4-(1H-indazol-3-yl)benzamido)butanoate
• 英文别名: methyl 4-[[4-(1H-indazol-3-yl)benzoyl]amino]butanoate
• CAS: 1032262-46-6
• 化学式: C₁₉H₁₉N₃O₃
• 分子量: 337.378
• InChiKey: HPZVTBSWLRDLRO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  84.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4-(4-(1H-indazol-3-yl)benzamido)butanoate 在 甲醇 、 lithium hydroxide 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 以91%的产率得到4-(4-(1H-indazol-3-yl)benzamido)butanoic acid
  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 60.17h， 生成 methyl 4-(4-(1H-indazol-3-yl)benzamido)butanoate
  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

• 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.
• BI-DENTATE COMPOUNDS AS KINASE INHIBITORS
  申请人：Pellecchia Maurizio

  公开号：US20110172164A1

  公开（公告）日：2011-07-14

  The present disclosure provides compound having the general structure A or pharmaceutically acceptable salts thereof: Het-L-P  (A) wherein Het is an aromatic moiety comprising a heterocyclic structure mimicking ATP, P is a docking site derived peptide or a docking site peptide mimetic, and L is a linking moiety, wherein L links the ATP mimetic to the docking site peptide moiety. The compounds having the general structure A can serve as inhibitors of kinases, such as the kinases JNK, Erk and p38.
• US8431529B2
  申请人：——

  公开号：US8431529B2

  公开（公告）日：2013-04-30
• [EN] BI-DENTATE COMPOUNDS AS KINASE INHIBITORS<br/>[FR] COMPOSÉS BIDENTATES EN TANT QU'INHIBITEURS DE LA KINASE
  申请人：SANFORD BURNHAM MED RES INST

  公开号：WO2012083092A2

  公开（公告）日：2012-06-21

  The present disclosure provides compound having the general structure A or pharmaceutically acceptable salts thereof: Het-L-P (A) wherein Het is an aromatic moiety comprising a heterocyclic structure mimicking ATP, P is a docking site derived peptide or a docking site peptide rnimetic, and L is a linking moiety, wherein L links the ATP mimetic to the docking site peptide moiety. The compounds having the general structure A can serve as inhibitors of kinases, such as the kinases JNK, Erk and p38.
• 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.