(E)-3-[2-[(4-aminophenyl)carbamoyl]vinyl]-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester | 246861-74-5

• 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: (E)-3-[2-[(4-aminophenyl)carbamoyl]vinyl]-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester
• 英文别名: ethyl 3-[(E)-3-(4-aminoanilino)-3-oxoprop-1-enyl]-4,6-dichloro-1H-indole-2-carboxylate
• CAS: 246861-74-5
• 化学式: C₂₀H₁₇Cl₂N₃O₃
• 分子量: 418.279
• InChiKey: JTAGCCOWNWGKNM-BQYQJAHWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  97.2
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (E)-3-[2-[(4-aminophenyl)carbamoyl]vinyl]-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester 在 lithium hydroxide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 (E)-4,6-dichloro-3-[2-[(4-ureidophenyl)carbamoyl]vinyl]-1H-indole-2-carboxylic acid
  参考文献：
  名称：

  Substituted Analogues of GV150526 as Potent Glycine Binding Site Antagonists in Animal Models of Cerebral Ischemia

  摘要：

  A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant; neuroprotective effect was seen in this model postischamia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.

  DOI：

  10.1021/jm980576n
• 作为产物：
  描述：

  4,6-二氯-3-甲酰基-1H-吲哚-2-甲酸乙酯 在 甲酸 、 2,2'-二硫二吡啶 、 三苯基膦 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 32.0h， 生成 (E)-3-[2-[(4-aminophenyl)carbamoyl]vinyl]-4,6-dichloro-1H-indole-2-carboxylic acid ethyl ester
  参考文献：
  名称：

  取代的吲哚-2-羧酸盐作为体内有效的拮抗剂，对苯丙氨酸不敏感的甘氨酸结合位点。

  摘要：

  合成了一系列在吲哚核的C-3位置带有合适链的吲哚-2-羧酸盐，并使用[3H]甘氨酸结合测定对体外亲和力进行了评估，并通过抑制N-诱导的惊厥来对体内效力进行了评估。小鼠中的D-天冬氨酸甲酯（NMDA）。3- [2-[（（苯基氨基）羰基]乙烯基] -4,6-二氯吲哚-2-羧酸（8）是对苯丙氨酸不敏感的甘氨酸结合位点的拮抗剂（对[3H] TCP的结合进行非竞争性抑制，pA2 = 8.1），显示出对甘氨酸结合位点的纳摩尔亲和力（pKi = 8.5），并具有高谷氨酸受体选择性（相对于NMDA，AMPA和海藻酸酯结合位点的亲和力> 1000倍）。当通过静脉和口服途径给药时（ED50 = 0.06和6 mg / kg，分别）。研究了取代基对C-3侧链的末端苯环的影响。QSAR分析表明，pKi值随亲脂性和取代基的空间体积而降低，并随存在于末端苯环对位的基团的电子供体共振效应而增加。根据这些结果，C-3侧链

  DOI：

  10.1021/jm960644a

文献信息

• Substituted Indole-2-carboxylates as <i>in Vivo</i> Potent Antagonists Acting as the Strychnine-Insensitive Glycine Binding Site
  作者：Romano Di Fabio、Anna M. Capelli、Nadia Conti、Alfredo Cugola、Daniele Donati、Aldo Feriani、Paola Gastaldi、Giovanni Gaviraghi、Cheryl T. Hewkin、Fabrizio Micheli、Andrea Missio、Manolo Mugnaini、Angelo Pecunioso、Anna M. Quaglia、Emiliangelo Ratti、Luciana Rossi、Giovanna Tedesco、David G. Trist、Angelo Reggiani

  DOI：10.1021/jm960644a

  日期：1997.3.1

  strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both

  合成了一系列在吲哚核的C-3位置带有合适链的吲哚-2-羧酸盐，并使用[3H]甘氨酸结合测定对体外亲和力进行了评估，并通过抑制N-诱导的惊厥来对体内效力进行了评估。小鼠中的D-天冬氨酸甲酯（NMDA）。3- [2-[（（苯基氨基）羰基]乙烯基] -4,6-二氯吲哚-2-羧酸（8）是对苯丙氨酸不敏感的甘氨酸结合位点的拮抗剂（对[3H] TCP的结合进行非竞争性抑制，pA2 = 8.1），显示出对甘氨酸结合位点的纳摩尔亲和力（pKi = 8.5），并具有高谷氨酸受体选择性（相对于NMDA，AMPA和海藻酸酯结合位点的亲和力> 1000倍）。当通过静脉和口服途径给药时（ED50 = 0.06和6 mg / kg，分别）。研究了取代基对C-3侧链的末端苯环的影响。QSAR分析表明，pKi值随亲脂性和取代基的空间体积而降低，并随存在于末端苯环对位的基团的电子供体共振效应而增加。根据这些结果，C-3侧链
• Substituted Analogues of GV150526 as Potent Glycine Binding Site Antagonists in Animal Models of Cerebral Ischemia
  作者：Romano Di Fabio、Nadia Conti、Elisabetta De Magistris、Aldo Feriani、Stefano Provera、Fabio Maria Sabbatini、Angelo Reggiani、Luca Rovatti、Robert J. Barnaby

  DOI：10.1021/jm980576n

  日期：1999.9.1

  A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant; neuroprotective effect was seen in this model postischamia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.