3-(4-amino-1-piperidin-3-ylpyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclohexylbenzamide;hydrochloride | 1407967-14-9

• 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-piperidin-3-ylpyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclohexylbenzamide;hydrochloride
• CAS: 1407967-14-9
• 化学式: C₂₃H₂₉N₇O*ClH
• 分子量: 455.99
• InChiKey: RUXKCVALPPYSPP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.48
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  111
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(4-amino-1-piperidin-3-ylpyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclohexylbenzamide;hydrochloride 、 乙酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以42%的产率得到3-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclohexylbenzamide
  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：

  3-[4-amino-3-(3-carboxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylicacid tert-butyl ester 在 盐酸 、 N,N'-羰基二咪唑 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 1.5h， 生成 3-(4-amino-1-piperidin-3-ylpyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclohexylbenzamide;hydrochloride
  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