4-(1H-indazol-3-yl)benzoic acid | 1018788-84-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(1H-indazol-3-yl)benzoic acid
• CAS: 1018788-84-5
• 化学式: C₁₄H₁₀N₂O₂
• 分子量: 238.246
• InChiKey: NYIVQYRLZKFCMF-UHFFFAOYSA-N

物化性质

• 沸点：
  517.9±33.0 °C(Predicted)
• 密度：
  1.377±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  66
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(1H-indazol-3-yl)benzoic acid 在 水 、 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 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 38.0h， 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
• 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 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 甲苯 、 乙腈 为溶剂， 反应 40.17h， 生成 4-(1H-indazol-3-yl)benzoic 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

• [EN] BIDENTATE-BINDING MODULATORS OF LRRK2 AND JNK KINASES<br/>[FR] MODULATEURS DES LIAISONS BIDENTÉES DES KINASES LRRK2 ET JNK
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2014200682A1

  公开（公告）日：2014-12-18

  Both JNK and LRRK2 are associated with Parkinson's disease (PD), myocardial infarction (Ml), and other medical disorders. Here we report a reasonably selective and potent kinase inhibitors (e.g., compounds 6 and 10) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. 6 also exhibited good cell potency, inhibited LRRK2:G2019S induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families.

  JNK和LRRK2都与帕金森病（PD）、心肌梗死（MI）和其他医学疾病相关联。在这里，我们报告了一种相对选择性和有效的激酶抑制剂（例如，化合物6和10），它们结合了JNK和LRRK2（双重抑制剂）。采用一种双齿结合策略，同时利用ATP铰链结合和ATP口袋外的独特蛋白表面位点，用于设计和识别这种抑制剂。化合物6是一种强效的JNK3和适度的LRRK2双重抑制剂，酶IC50值分别为12 nM和99 nM（LRRK2-G2019S）。6还表现出良好的细胞效力，在SHSY5Y细胞中抑制了LRRK2：G2019S诱导的线粒体功能障碍，并被证明对来自代表性激酶家族的116种激酶面板具有相当的选择性。
• [EN] BI-DENTATE COMPOUNDS AS KINASE INHIBITORS<br/>[FR] COMPOSÉS BIDENTATE EN TANT QU'INHIBITEURS DE KINASE
  申请人：BURNHAM INST MEDICAL RESEARCH

  公开号：WO2009018490A1

  公开（公告）日：2009-02-05

  The present invention 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.

  本发明提供了具有一般结构A或其药学上可接受的盐的化合物：Het-L-P（A），其中Het是包含模拟ATP的杂环结构的芳香基团，P是源自肽的结合位点或模拟结合位点的肽，L是连接基团，其中L将ATP模拟物连接到结合位点肽基团。具有一般结构A的化合物可以作为激酶的抑制剂，例如激酶JNK、Erk和P38。
• Design, Synthesis and Anticandidal Evaluation of Indazole and Pyrazole Derivatives
  作者：Karen Rodríguez-Villar、Alicia Hernández-Campos、Lilián Yépez-Mulia、Teresita del Rosario Sainz-Espuñes、Olivia Soria-Arteche、Juan Francisco Palacios-Espinosa、Francisco Cortés-Benítez、Martha Leyte-Lugo、Bárbara Varela-Petrissans、Edgar A. Quintana-Salazar、Jaime Pérez-Villanueva

  DOI：10.3390/ph14030176

  日期：——

  a series of indazole and pyrazole derivatives were designed in this work, employing bioisosteric replacement, homologation, and molecular simplification as new anticandidal agents. Compounds were synthesized and evaluated against C. albicans, C. glabrata, and C. tropicalis strains. The series of 3-phenyl-1H-indazole moiety (10a–i) demonstrated to have the best broad anticandidal activity. Particularly

  由念珠菌属酵母引起的念珠菌病是浅表和粘膜感染的第二大原因，也是血液感染的第四大原因。尽管可获得一些治疗念珠菌病的抗真菌药物，但对当前疗法的耐药菌株正在出现。因此，寻找新的候选化合物无疑是当务之急。在这方面，在这项工作中设计了一系列吲唑和吡唑衍生物，采用生物等位取代，同源化和分子简化作为新的抗候选药物。合成化合物并针对白色念珠菌，光滑念珠菌和热带念珠菌菌株进行评估。3-苯基-1 H-吲唑部分系列（10a–i被证明具有最佳的广泛的抗候选活性。特别地，具有N，N-二乙基羧酰胺取代基的化合物10g对白色念珠菌和对咪康唑敏感的和抗性的光滑念珠菌物种最具活性。因此，3-苯基-1 H-吲唑支架代表了开发具有新化学型的新抗候选药物的机会。
• A facile route to 1<i>H</i>- and 2<i>H</i>-indazoles from readily accessible acyl hydrazides by exploiting a novel aryne-based molecular rearrangement
  作者：André Shamsabadi、Vijay Chudasama

  DOI：10.1039/c8cc06556j

  日期：——

  A facile procedure for the conversion of readily accessible acyl hydrazides into 1H and 2H-indazoles via a novel aryne-based molecular rearrangement pathway.

  一种简便的将易得的酰基肼转化为1H和2H-吲唑的程序，通过一种基于新颖芳炔的分子重排途径。
• BIDENTATE-BINDING MODULATORS OF LRRK2 AND JNK KINASES
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：US20160185818A1

  公开（公告）日：2016-06-30

  Both JNK and LRRK2 are associated with Parkinson's disease (PD), myocardial infarction (MI), and other medical disorders. Here we report a reasonably selective and potent kinase inhibitors (e.g., compounds 6 and 10) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. 6 also exhibited good cell potency, inhibited LRRK2:G2019S induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families.

  JNK和LRRK2都与帕金森病（PD）、心肌梗死（MI）和其他医学疾病有关。在这里，我们报告了一种相对选择性和有效的激酶抑制剂（例如化合物6和10），它们结合了JNK和LRRK2（双重抑制剂）。采用一种双齿配体结合策略，同时利用ATP铰链结合和ATP口袋外的独特蛋白表面位点，设计和鉴定了这种抑制剂。化合物6是一种强效的JNK3和适度的LRRK2双重抑制剂，其酶IC50值分别为12 nM和99 nM（LRRK2-G2019S）。6还表现出良好的细胞效力，在SHSY5Y细胞中抑制了LRRK2：G2019S诱导的线粒体功能障碍，并被证明在代表性激酶家族的116个激酶面板中相对选择性较好。