2-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)indolin-2-yl)acetic acid

• 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: 2-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)indolin-2-yl)acetic acid
• 英文别名: ROR|At agonist 1；2-[6-[3-(difluoromethoxy)-5-fluorophenyl]-1-[3-(trifluoromethyl)phenyl]sulfonyl-2,3-dihydroindol-2-yl]acetic acid
• 化学式: C₂₄H₁₇F₆NO₅S
• 分子量: 545.459
• InChiKey: UAFXMLYFRFORFY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  92.3
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  氮杂环丁烷-3-醇 、 2-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)indolin-2-yl)acetic acid 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 为溶剂， 以65%的产率得到2-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)indolin-2-yl)-1-(3-hydroxyazetidin-1-yl)ethanone
  参考文献：
  名称：

  Discovery of aryl-substituted indole and indoline derivatives as RORγt agonists

  摘要：

  A series of aryl-substituted indole and indoline derivatives were discovered as novel ROR gamma t agonists by a scaffold-based hybridization of the reported ROR gamma t agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent ROR gamma t agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC50 of 20.8 +/- 1.5 nM, the (S)-enantiomer (EC50 = 16.1 +/- 4.5 nM) of which was 17 times more potent than the (R) counterpart (EC50 = 286 +/- 30.4 nM) in ROR gamma dual FRET assay. The cell based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC50 of 247 +/- 33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t(1/2) = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds. Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of ROR gamma t agonist for cancer immunotherapy. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111589
• 作为产物：
  描述：

  3-三氟甲基苯磺酰氯 在 4-二甲氨基吡啶 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium carbonate 、 N,N-二异丙基乙胺 、 lithium hydroxide 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 29.0h， 生成 2-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)indolin-2-yl)acetic acid
  参考文献：
  名称：

  Discovery of aryl-substituted indole and indoline derivatives as RORγt agonists

  摘要：

  A series of aryl-substituted indole and indoline derivatives were discovered as novel ROR gamma t agonists by a scaffold-based hybridization of the reported ROR gamma t agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent ROR gamma t agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC50 of 20.8 +/- 1.5 nM, the (S)-enantiomer (EC50 = 16.1 +/- 4.5 nM) of which was 17 times more potent than the (R) counterpart (EC50 = 286 +/- 30.4 nM) in ROR gamma dual FRET assay. The cell based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC50 of 247 +/- 33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t(1/2) = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds. Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of ROR gamma t agonist for cancer immunotherapy. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111589

文献信息

• Discovery of aryl-substituted indole and indoline derivatives as RORγt agonists
  作者：Yan Zhu、Nannan Sun、Mingcheng Yu、Huimin Guo、Qiong Xie、Yonghui Wang

  DOI：10.1016/j.ejmech.2019.111589

  日期：2019.11

  A series of aryl-substituted indole and indoline derivatives were discovered as novel ROR gamma t agonists by a scaffold-based hybridization of the reported ROR gamma t agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent ROR gamma t agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC50 of 20.8 +/- 1.5 nM, the (S)-enantiomer (EC50 = 16.1 +/- 4.5 nM) of which was 17 times more potent than the (R) counterpart (EC50 = 286 +/- 30.4 nM) in ROR gamma dual FRET assay. The cell based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC50 of 247 +/- 33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t(1/2) = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds. Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of ROR gamma t agonist for cancer immunotherapy. (C) 2019 Elsevier Masson SAS. All rights reserved.