N-[(2S)-1-[1-[3,4-bis(fluoranyl)phenyl]-4-oxidanylidene-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]-5-fluoranyl-1H-indole-2-carboxamide;2,2,2-tris(fluoranyl)ethanoic acid | 1244640-04-7

• 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: N-[(2S)-1-[1-[3,4-bis(fluoranyl)phenyl]-4-oxidanylidene-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]-5-fluoranyl-1H-indole-2-carboxamide;2,2,2-tris(fluoranyl)ethanoic acid
• 英文别名: N-[(2S)-1-[1-(3,4-difluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]-5-fluoro-1H-indole-2-carboxamide
• CAS: 1244640-04-7
• 化学式: C₂₅H₂₆F₃N₅O₂
• 分子量: 485.509
• InChiKey: HWHBSTPKWDIKIG-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  80.5
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-[(2S)-1-[1-[3,4-bis(fluoranyl)phenyl]-4-oxidanylidene-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]-5-fluoranyl-1H-indole-2-carboxamide;2,2,2-tris(fluoranyl)ethanoic acid 、 三氟乙酸 以 水 、 乙腈 为溶剂， 反应 0.08h， 生成 N-[(2S)-1-[1-(3,4-difluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]-5-fluoro-1H-indole-2-carboxamide;2,2,2-trifluoroacetic acid
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Halogenated N-(2-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: Discovery of an Isoform-Selective Small Molecule Phospholipase D2 Inhibitor

  摘要：

  Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD I and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion, and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (> 1700-fold selective), and moderately PLD2-preferring (> 10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC(50) = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date. N-(2-(1-(3-fluorophenyl)-4-oxo-1.3.8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.

  DOI：

  10.1021/jm100814g
• 作为产物：
  描述：

  (S)-8-(2-aminopropyl)-1-(3,4-difluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one dihydrochloride 、 5-氟-1H-吲哚-2-甲酰氯 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-[(2S)-1-[1-[3,4-bis(fluoranyl)phenyl]-4-oxidanylidene-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]-5-fluoranyl-1H-indole-2-carboxamide;2,2,2-tris(fluoranyl)ethanoic acid
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Halogenated N-(2-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: Discovery of an Isoform-Selective Small Molecule Phospholipase D2 Inhibitor

  摘要：

  Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD I and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion, and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (> 1700-fold selective), and moderately PLD2-preferring (> 10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC(50) = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date. N-(2-(1-(3-fluorophenyl)-4-oxo-1.3.8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.

  DOI：

  10.1021/jm100814g

文献信息

• Design, Synthesis, and Biological Evaluation of Halogenated <i>N</i>-(2-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: Discovery of an Isoform-Selective Small Molecule Phospholipase D2 Inhibitor
  作者：Robert R. Lavieri、Sarah A. Scott、Paige E. Selvy、Kwangho Kim、Satyawan Jadhav、Ryan D. Morrison、J. Scott Daniels、H. Alex Brown、Craig W. Lindsley

  DOI：10.1021/jm100814g

  日期：2010.9.23

  Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD I and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion, and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (> 1700-fold selective), and moderately PLD2-preferring (> 10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC(50) = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date. N-(2-(1-(3-fluorophenyl)-4-oxo-1.3.8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.