5-chloro-N-((4-(dimethylamino)phenyl)ethyl)-3-ethyl-1H-indole-2-carboxamide | 1377838-08-8

• 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: 5-chloro-N-((4-(dimethylamino)phenyl)ethyl)-3-ethyl-1H-indole-2-carboxamide
• 英文别名: 5-chloro-N-(2-(4-dimethylaminophenyl)ethyl)-3-ethyl-1H-indole-2-carboxamide；5-chloro-N-[2-[4-(dimethylamino)phenyl]ethyl]-3-ethyl-1H-indole-2-carboxamide
• CAS: 1377838-08-8
• 化学式: C₂₁H₂₄ClN₃O
• 分子量: 369.894
• InChiKey: WVXDJOGNHLCWST-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  48.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  5-氯吲哚-2-羧酸乙酯 在 三乙基硅烷 、 aluminum (III) chloride 、 水 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 5-chloro-N-((4-(dimethylamino)phenyl)ethyl)-3-ethyl-1H-indole-2-carboxamide
  参考文献：
  名称：

  Structure–Activity Relationship Study of Indole-2-carboxamides Identifies a Potent Allosteric Modulator for the Cannabinoid Receptor 1 (CB1)

  摘要：

  The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor. 5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569; 1) represents a new class of indole-2-carboxamides that exhibit allostery of CBI. To better understand 0 the SAR, a group of indole-2-carboxamide analogues were synthesized and assessed for allostery of the CB1 receptor. We found that within the structure of indole-2-carboxamides, the presence of the indole ring is preferred for maintaining the modulator's high binding affinity for the allosteric site but not for generating allostery on the orthosteric site. However, the C3 substituents of the indole-2-carboxamides significantly impact the allostery of the ligand. A robust CBI allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-pentyl-1H-indole-2-carboxamide (11j) was identified. It showed an equilibrium dissociation constant (K-B) of 167.3 nM with a markedly high binding cooperativity factor (alpha = 16.55) and potent antagonism of agonist-induced GTP gamma S binding.

  DOI：

  10.1021/jm4009828

文献信息

• Indole-2-carboxamides as Allosteric Modulators of the Cannabinoid CB₁ Receptor
  作者：Francesco Piscitelli、Alessia Ligresti、Giuseppe La Regina、Antonio Coluccia、Ludovica Morera、Marco Allarà、Ettore Novellino、Vincenzo Di Marzo、Romano Silvestri

  DOI：10.1021/jm201485c

  日期：2012.6.14

  We synthesized new N-phenylethyl-1H-indole-2-carboxamides as the first SAR study of allosteric modulators of the CB1 receptor. The presence of the carboxamide functionality was required in order to obtain a stimulatory effect. The maximum stimulatory activity on CB1 was exerted by carboxamides 13 (EC50 = 50 nM) and 21 (EC50 = 90 nM) bearing a dimethylamino or piperidinyl group, respectively, at position

  我们合成了新的N-苯乙基-1 H-吲哚-2-羧酰胺作为CB 1受体的变构调节剂的第一个SAR研究。为了获得刺激作用，需要羧酰胺官能团的存在。CB 1的最大刺激活性是由分别在苯乙部分的4位带有二甲氨基或哌啶基的羧酰胺13（EC 50 = 50 nM）和21（EC 50 = 90 nM）发挥的。吲哚的5。
• Structure–Activity Relationship Study of Indole-2-carboxamides Identifies a Potent Allosteric Modulator for the Cannabinoid Receptor <b>1</b> (CB1)
  作者：Mariam M. Mahmoud、Hamed I. Ali、Kwang H. Ahn、Aparna Damaraju、Sushma Samala、Venkata K. Pulipati、Srikanth Kolluru、Debra A. Kendall、Dai Lu

  DOI：10.1021/jm4009828

  日期：2013.10.24

  The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor. 5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569; 1) represents a new class of indole-2-carboxamides that exhibit allostery of CBI. To better understand 0 the SAR, a group of indole-2-carboxamide analogues were synthesized and assessed for allostery of the CB1 receptor. We found that within the structure of indole-2-carboxamides, the presence of the indole ring is preferred for maintaining the modulator's high binding affinity for the allosteric site but not for generating allostery on the orthosteric site. However, the C3 substituents of the indole-2-carboxamides significantly impact the allostery of the ligand. A robust CBI allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-pentyl-1H-indole-2-carboxamide (11j) was identified. It showed an equilibrium dissociation constant (K-B) of 167.3 nM with a markedly high binding cooperativity factor (alpha = 16.55) and potent antagonism of agonist-induced GTP gamma S binding.