5-Methoxy-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid (3-pyridin-3-yl-phenyl)-amide

• 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-Methoxy-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid (3-pyridin-3-yl-phenyl)-amide
• 英文别名: 5-methoxy-N-(3-pyridin-3-ylphenyl)-6-(trifluoromethyl)-2,3-dihydroindole-1-carboxamide
• 化学式: C₂₂H₁₈F₃N₃O₂
• 分子量: 413.399
• InChiKey: QAHSLFRXUDDOIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  54.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-氨基苯硼酸 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 5-Methoxy-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid (3-pyridin-3-yl-phenyl)-amide
  参考文献：
  名称：

  Biarylcarbamoylindolines Are Novel and Selective 5-HT_2C Receptor Inverse Agonists:  Identification of 5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a Potential Antidepressant/Anxiolytic Agent

  摘要：

  The evolution, synthesis, and biological activity of a novel series of 5-HT2C receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT2C affinity and selectivity over 5-HT2A receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT2B receptor. Compounds from this series are inverse agonists at the human cloned 5-HT2C receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

  DOI：

  10.1021/jm990388c

文献信息

• A Divergent SAR Study Allows Optimization of a Potent 5-HT_2c Inhibitor to a Promising Antimalarial Scaffold
  作者：Félix Calderón、Jaume Vidal-Mas、Jeremy Burrows、Juan Carlos de la Rosa、María Belén Jiménez-Díaz、Teresa Mulet、Sara Prats、Jorge Solana、Michael Witty、Francisco Javier Gamo、Esther Fernández

  DOI：10.1021/ml300008j

  日期：2012.5.10

  From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of the most promising hits was the TCMDC-139046, a molecule presenting an indoline core, which is well-known for its anxiolytic properties by interacting with serotonin antagonist receptors 5-HT2. The inhibition of this target will complicate the clinical development of these compounds as antimalarials. Herein, we present the antimalarial profile of this series and our efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency. By using a double-divergent structure-activity relationship analysis, we have obtained a novel lead compound harboring an indoline core.
• Biarylcarbamoylindolines Are Novel and Selective 5-HT_2C Receptor Inverse Agonists:  Identification of 5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a Potential Antidepressant/Anxiolytic Agent
  作者：Steven M. Bromidge、Steven Dabbs、David T. Davies、Susannah Davies、D. Malcolm Duckworth、Ian T. Forbes、Laramie M. Gaster、Peter Ham、Graham E. Jones、Frank D. King、Keith R. Mulholland、Damian V. Saunders、Paul A. Wyman、Frank E. Blaney、Stephen E. Clarke、Thomas P. Blackburn、Vicky Holland、Guy A. Kennett、Sean Lightowler、Derek N. Middlemiss、Brenda Trail、Graham J. Riley、Martyn D. Wood

  DOI：10.1021/jm990388c

  日期：2000.3.1

  The evolution, synthesis, and biological activity of a novel series of 5-HT2C receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT2C affinity and selectivity over 5-HT2A receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT2B receptor. Compounds from this series are inverse agonists at the human cloned 5-HT2C receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.