N,N-dibutyl-2-[2-(4-methoxyphenyl)-1H-indol-3-yl]-2-oxoacetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N,N-dibutyl-2-[2-(4-methoxyphenyl)-1H-indol-3-yl]-2-oxoacetamide
• 化学式: C₂₅H₃₀N₂O₃
• 分子量: 406.525
• InChiKey: YQJUZZHHIAJESY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  62.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N,N-dibutyl-2-[2-(4-methoxyphenyl)-1H-indol-3-yl]-2-oxoacetamide 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以68%的产率得到N,N-dibutyl-2-[2-(4-hydroxyphenyl)-1H-indol-3-yl]-2-oxoacetamide
  参考文献：
  名称：

  Deepening the Topology of the Translocator Protein Binding Site by Novel N,N-Dialkyl-2-arylindol-3-ylglyoxylamides

  摘要：

  As a continuation of our studies on 2-phenylindol-3-ylglyoxylamides as potent and selective translocator protein (TSPO) ligands, two subsets of novel derivatives, featuring hydrophilic group (OH, NH2, COOH) at the para-position of the pendent 2-phenyl ring (8-16) or different 2-aryl moieties, namely, 3-thienyl, p-biphenyl, 2-naphthyl (23-35), were synthesized and biologically evaluated, some of them showing K-i values in the subnanomolar range and the 2-naphthyl group performance being the best. The resulting SARs confirmed the key role played by interactions taking place between ligands and the lipophilic Li pocket of the TSPO binding site. Docking simulations were performed on the most potent compound of the present series (29) exploiting the recently available 3D structures of TSPO bound to its standard ligand (PK11195). Our theoretical model was fully consistent with SARs of the newly investigated as well of the previously reported 2-phenylindol-3-ylglyoxylamide derivatives.

  DOI：

  10.1021/acs.jmedchem.5b00689
• 作为产物：
  描述：

  2-(4-甲氧基苯基)-1H-吲哚 在 三乙胺 作用下， 以 乙醚 、 甲苯 为溶剂， 生成 N,N-dibutyl-2-[2-(4-methoxyphenyl)-1H-indol-3-yl]-2-oxoacetamide
  参考文献：
  名称：

  TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being

  摘要：

  甾类运载蛋白18 kDa转运体（TSPO）是一种新兴的、有吸引力的治疗神经系统多种病理状况的工具。在这里，我们评估了13种高亲和力的TSPO配体，它们属于我们之前描述的N,N-二烷基-2-苯基吲哚-3-基甘氧酰胺（PIGA）类，它们的潜在能力能够影响细胞氧化代谢活性/增殖指数，这被用作评估星形胶质细胞健康状况的指标。最活跃的PIGA配体还被评估了在孕烯醇酮生产方面的甾体生成活性，并与大鼠和人类模型中的代谢指数相关联。结果显示，氧化代谢活性/增殖指数的增加与药物诱导的甾体生成刺激之间存在正相关关系。使用氨基己烯比密定，一种特异性抑制甾体生物合成第一步的抑制剂，证明了甾体分子在介导PIGA配体的代谢效应中的特定作用。最有前景的甾体生成PIGA配体是2-萘基衍生物，它们在目标上的停留时间较长，与我们的先前数据一致。总之，TSPO配体诱导的神经营养激素生成与星形胶质细胞的健康有关。

  DOI：

  10.3390/ijms17071028

文献信息

• Deepening the Topology of the Translocator Protein Binding Site by Novel <i>N</i>,<i>N</i>-Dialkyl-2-arylindol-3-ylglyoxylamides
  作者：Elisabetta Barresi、Agostino Bruno、Sabrina Taliani、Sandro Cosconati、Eleonora Da Pozzo、Silvia Salerno、Francesca Simorini、Simona Daniele、Chiara Giacomelli、Anna Maria Marini、Concettina La Motta、Luciana Marinelli、Barbara Cosimelli、Ettore Novellino、Giovanni Greco、Federico Da Settimo、Claudia Martini

  DOI：10.1021/acs.jmedchem.5b00689

  日期：2015.8.13

  As a continuation of our studies on 2-phenylindol-3-ylglyoxylamides as potent and selective translocator protein (TSPO) ligands, two subsets of novel derivatives, featuring hydrophilic group (OH, NH2, COOH) at the para-position of the pendent 2-phenyl ring (8-16) or different 2-aryl moieties, namely, 3-thienyl, p-biphenyl, 2-naphthyl (23-35), were synthesized and biologically evaluated, some of them showing K-i values in the subnanomolar range and the 2-naphthyl group performance being the best. The resulting SARs confirmed the key role played by interactions taking place between ligands and the lipophilic Li pocket of the TSPO binding site. Docking simulations were performed on the most potent compound of the present series (29) exploiting the recently available 3D structures of TSPO bound to its standard ligand (PK11195). Our theoretical model was fully consistent with SARs of the newly investigated as well of the previously reported 2-phenylindol-3-ylglyoxylamide derivatives.
• TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being
  作者：Eleonora Da Pozzo、Chiara Giacomelli、Barbara Costa、Chiara Cavallini、Sabrina Taliani、Elisabetta Barresi、Federico Da Settimo、Claudia Martini

  DOI：10.3390/ijms17071028

  日期：——

  The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being.

  甾类运载蛋白18 kDa转运体（TSPO）是一种新兴的、有吸引力的治疗神经系统多种病理状况的工具。在这里，我们评估了13种高亲和力的TSPO配体，它们属于我们之前描述的N,N-二烷基-2-苯基吲哚-3-基甘氧酰胺（PIGA）类，它们的潜在能力能够影响细胞氧化代谢活性/增殖指数，这被用作评估星形胶质细胞健康状况的指标。最活跃的PIGA配体还被评估了在孕烯醇酮生产方面的甾体生成活性，并与大鼠和人类模型中的代谢指数相关联。结果显示，氧化代谢活性/增殖指数的增加与药物诱导的甾体生成刺激之间存在正相关关系。使用氨基己烯比密定，一种特异性抑制甾体生物合成第一步的抑制剂，证明了甾体分子在介导PIGA配体的代谢效应中的特定作用。最有前景的甾体生成PIGA配体是2-萘基衍生物，它们在目标上的停留时间较长，与我们的先前数据一致。总之，TSPO配体诱导的神经营养激素生成与星形胶质细胞的健康有关。