3-{4-amino-3-[3-(4-isopropylphenylcarbamoyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl}piperidine-1-carboxylic acid tert-butyl ester | 1407967-09-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-{4-amino-3-[3-(4-isopropylphenylcarbamoyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl}piperidine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (3R)-3-[4-amino-3-[3-[(4-propan-2-ylphenyl)carbamoyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate
• CAS: 1407967-09-2
• 化学式: C₃₁H₃₇N₇O₃
• 分子量: 555.68
• InChiKey: DOCAESMHRNIIPN-XMMPIXPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  41
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-{4-amino-3-[3-(4-isopropylphenylcarbamoyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl}piperidine-1-carboxylic acid tert-butyl ester 在 盐酸 、 三乙胺 、 potassium iodide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 1.58h， 生成 3-[4-amino-1-[(3R)-1-[(E)-4-(methylamino)but-2-enoyl]piperidin-3-yl]pyrazolo[3,4-d]pyrimidin-3-yl]-N-(4-propan-2-ylphenyl)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
• 作为产物：
  描述：

  4-异丙基苯胺 、 3-[4-amino-3-(3-carboxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylicacid tert-butyl ester 在 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以76%的产率得到3-{4-amino-3-[3-(4-isopropylphenylcarbamoyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl}piperidine-1-carboxylic acid tert-butyl ester
  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.