3-butyl-5-chloro-1H-indole-2-carboxylic acid | 1584144-42-2

• 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: 3-butyl-5-chloro-1H-indole-2-carboxylic acid
• CAS: 1584144-42-2
• 化学式: C₁₃H₁₄ClNO₂
• 分子量: 251.713
• InChiKey: RRDXDUQUTIFJHZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.86
• 重原子数：
  17.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  53.09
• 氢给体数：
  2.0
• 氢受体数：
  1.0

反应信息

• 作为反应物：
  描述：

  2-(4-哌啶-1-基苯基)乙胺 、 3-butyl-5-chloro-1H-indole-2-carboxylic acid 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以31.9%的产率得到5-chloro-3-butyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide
  参考文献：
  名称：

  Optimization of Chemical Functionalities of Indole-2-carboxamides To Improve Allosteric Parameters for the Cannabinoid Receptor 1 (CB1)

  摘要：

  5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (1; ORG27569) is a prototypical allosteric modulator for the cannabinoid type I receptor (CBI). Here, we reveal key structural requirements of indole-2-carboxamides for allosteric modulation of CBI: a critical chain length at the C3-position, an electron withdrawing group at the CS-position, the length of the linker between the amide bond and the phenyl ring B, and the amino substituent on the phenyl ring B. These significantly impact the binding affinity (K-B) and the binding cooperativity (alpha). A potent CB1 allosteric modulator 5-chloro-N-(4(dimethylamino)phenethyl)-3-propyl-1H-indole-2-carboxamide (12d) was identified. It exhibited a K-B of 259.3 nM with a strikingly high binding alpha of 24.5. We also identified 5-chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-indole-2-carboxamide (120 with a K-B of 89.1 nM, which is among the lowest K-B values obtained for any allosteric modulator of CB1. These positive allosteric modulators of orthosteric agonist binding nonetheless antagonized the agonist-induced G-protein coupling to the CB1 receptor, yet induced beta-arrestin mediated ERK/2 phosphorylation.

  DOI：

  10.1021/jm5000112
• 作为产物：
  描述：

  ethyl 3-butyryl-5-chloroindole-2-carboxylate 在 三乙基硅烷 、 三氟乙酸 、 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 2.0h， 生成 3-butyl-5-chloro-1H-indole-2-carboxylic acid
  参考文献：
  名称：

  Optimization of Chemical Functionalities of Indole-2-carboxamides To Improve Allosteric Parameters for the Cannabinoid Receptor 1 (CB1)

  摘要：

  5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (1; ORG27569) is a prototypical allosteric modulator for the cannabinoid type I receptor (CBI). Here, we reveal key structural requirements of indole-2-carboxamides for allosteric modulation of CBI: a critical chain length at the C3-position, an electron withdrawing group at the CS-position, the length of the linker between the amide bond and the phenyl ring B, and the amino substituent on the phenyl ring B. These significantly impact the binding affinity (K-B) and the binding cooperativity (alpha). A potent CB1 allosteric modulator 5-chloro-N-(4(dimethylamino)phenethyl)-3-propyl-1H-indole-2-carboxamide (12d) was identified. It exhibited a K-B of 259.3 nM with a strikingly high binding alpha of 24.5. We also identified 5-chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-indole-2-carboxamide (120 with a K-B of 89.1 nM, which is among the lowest K-B values obtained for any allosteric modulator of CB1. These positive allosteric modulators of orthosteric agonist binding nonetheless antagonized the agonist-induced G-protein coupling to the CB1 receptor, yet induced beta-arrestin mediated ERK/2 phosphorylation.

  DOI：

  10.1021/jm5000112