ethyl 5-(1-(phenylsulfonyl)-1H-pyrazol-3-yl)-1-(2-(4-(trifluoromethoxy)phenoxy)ethyl)-1H-indole-2-carboxylate | 1614229-16-1

• 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: ethyl 5-(1-(phenylsulfonyl)-1H-pyrazol-3-yl)-1-(2-(4-(trifluoromethoxy)phenoxy)ethyl)-1H-indole-2-carboxylate
• CAS: 1614229-16-1
• 化学式: C₂₉H₂₄F₃N₃O₆S
• 分子量: 599.587
• InChiKey: HCEOHWNEZNMJHO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  42.0
• 可旋转键数：
  10.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  101.65
• 氢给体数：
  0.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  ethyl 5-(1-(phenylsulfonyl)-1H-pyrazol-3-yl)-1-(2-(4-(trifluoromethoxy)phenoxy)ethyl)-1H-indole-2-carboxylate 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以28%的产率得到5-(1H-pyrazol-3-yl)-1-(2-(4-(trifluoromethoxy)phenoxy)ethyl)-1H-indole-2-carboxylic acid
  参考文献：
  名称：

  Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain

  摘要：

  We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

  DOI：

  10.1021/jm5006429
• 作为产物：
  描述：

  5-溴吲哚-2-羧酸乙酯 在 2-双环己基膦-2',6'-二甲氧基联苯 、 偶氮二甲酸二异丙酯 、 potassium acetate 、 palladium diacetate 、 potassium carbonate 、 三苯基膦 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 、 水 、 甲苯 为溶剂， 生成 ethyl 5-(1-(phenylsulfonyl)-1H-pyrazol-3-yl)-1-(2-(4-(trifluoromethoxy)phenoxy)ethyl)-1H-indole-2-carboxylate
  参考文献：
  名称：

  Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain

  摘要：

  We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

  DOI：

  10.1021/jm5006429