3-[4-amino-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidin-3-yl]-N-[2-(4-fluorophenyl)ethyl]benzamide | 1407966-84-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-[4-amino-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidin-3-yl]-N-[2-(4-fluorophenyl)ethyl]benzamide
• CAS: 1407966-84-0
• 化学式: C₂₈H₂₈FN₇O₂
• 分子量: 513.574
• InChiKey: JPSPTTRNCXPGQE-JOCHJYFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (S)-1-叔丁氧羰基-3-羟基哌啶 在 盐酸 、 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 偶氮二甲酸二异丙酯 、 水 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 3-[4-amino-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazolo[3,4-d]pyrimidin-3-yl]-N-[2-(4-fluorophenyl)ethyl]benzamide
  参考文献：
  名称：

  Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood Assay

  摘要：

  We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.

  DOI：

  10.1021/jm301190s

文献信息

• Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood Assay
  作者：Christoph W. Zapf、Brian S. Gerstenberger、Li Xing、David C. Limburg、David R. Anderson、Nicole Caspers、Seungil Han、Ann Aulabaugh、Ravi Kurumbail、Subarna Shakya、Xin Li、Vikki Spaulding、Robert M. Czerwinski、Nilufer Seth、Quintus G. Medley

  DOI：10.1021/jm301190s

  日期：2012.11.26

  We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.