1-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(4-methyl piperazin-1-yl)ethan-1-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(4-methyl piperazin-1-yl)ethan-1-one
• 英文别名: 2-(4-methylpiperazin-1-yl)-1-[4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]piperidin-1-yl]ethanone
• 化学式: C₂₁H₂₈N₈O
• 分子量: 408.506
• InChiKey: BNNJDOUMEKWEAW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  86.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (4-氯-7H-吡咯并[2,3-D]嘧啶-7-基)甲基特戊酸酯 在 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 、 水 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基乙酰胺 为溶剂， 反应 21.0h， 生成 1-(4-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(4-methyl piperazin-1-yl)ethan-1-one
  参考文献：
  名称：

  Design, synthesis and anti-inflammatory evaluation of novel pyrrolo[2,3-d]pyrimidin derivatives as potent JAK inhibitors

  摘要：

  Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a-8p and 11 a-11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC50 value of 88.2 mu M against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1 beta. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.

  DOI：

  10.1016/j.bmc.2019.07.037

文献信息

• Design, synthesis and anti-inflammatory evaluation of novel pyrrolo[2,3-d]pyrimidin derivatives as potent JAK inhibitors
  作者：Feng Jiang、Linghe Zang、Xiuqi Miao、Fang Jia、Jie Wang、Minglin Zhu、Ping Gong、Nan Jiang、Xin Zhai

  DOI：10.1016/j.bmc.2019.07.037

  日期：2019.9

  Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a-8p and 11 a-11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC50 value of 88.2 mu M against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1 beta. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.