N'-(3,5-dichloropyridin-4-yl)-1H-indole-2-carbohydrazide | 1370287-02-7

• 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'-(3,5-dichloropyridin-4-yl)-1H-indole-2-carbohydrazide
• CAS: 1370287-02-7
• 化学式: C₁₄H₁₀Cl₂N₄O
• 分子量: 321.166
• InChiKey: HCOLVCUFXCVEBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  69.8
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3,5-二氯-4-碘吡啶 在 一水合肼 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 N'-(3,5-dichloropyridin-4-yl)-1H-indole-2-carbohydrazide
  参考文献：
  名称：

  Structure–Activity Relationships and Optimization of 3,5-Dichloropyridine Derivatives As Novel P2X₇Receptor Antagonists

  摘要：

  Screening of a library of chemical compounds showed that the dichloropyridine-based analogue 9 was a novel P2X(7) receptor antagonist. To optimize its activity, we assessed the structure-activity relationships (SAR) of 9, focusing on the hydrazide linker, the dichloropyridine skeleton, and the hydrophobic acyl (R-2) group. We found that the hydrazide linker and the 3,5-disubstituted chlorides in the pyridine skeleton were critical for P2X(7) antagonistic activity and that the presence of hydrophobic polycycloalkyl groups at the R-2 position optimized antagonistic activity. In the EtBr uptake assay in hP2X(7)-expressing HEK293 cells, the optimized antagonists, 5i and 52, had IC50 values of 4.9 and 13 nM, respectively. The antagonistic effects of 51 and 52 were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1 beta, by LPS/IFN-gamma/BzATP stimulation of THP-1 cells (IC50 = 1.3 and 9.2 nM, respectively). In addition, 52 strongly inhibited iNOS/COX-2 expression and NO production in THP-1 cells, further indicating that this compound blocks inflammatory signaling and suggesting that the dichloropyridine analogues may be useful in developing P2X(7) receptor targeted anti-inflammatory agents.

  DOI：

  10.1021/jm2012326

文献信息

• Structure–Activity Relationships and Optimization of 3,5-Dichloropyridine Derivatives As Novel P2X₇Receptor Antagonists
  作者：Won-Gil Lee、So-Deok Lee、Joong-Heui Cho、Younghwan Jung、Jeong-hyun Kim、Tran T. Hien、Keon-Wook Kang、Hyojin Ko、Yong-Chul Kim

  DOI：10.1021/jm2012326

  日期：2012.4.26

  Screening of a library of chemical compounds showed that the dichloropyridine-based analogue 9 was a novel P2X(7) receptor antagonist. To optimize its activity, we assessed the structure-activity relationships (SAR) of 9, focusing on the hydrazide linker, the dichloropyridine skeleton, and the hydrophobic acyl (R-2) group. We found that the hydrazide linker and the 3,5-disubstituted chlorides in the pyridine skeleton were critical for P2X(7) antagonistic activity and that the presence of hydrophobic polycycloalkyl groups at the R-2 position optimized antagonistic activity. In the EtBr uptake assay in hP2X(7)-expressing HEK293 cells, the optimized antagonists, 5i and 52, had IC50 values of 4.9 and 13 nM, respectively. The antagonistic effects of 51 and 52 were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1 beta, by LPS/IFN-gamma/BzATP stimulation of THP-1 cells (IC50 = 1.3 and 9.2 nM, respectively). In addition, 52 strongly inhibited iNOS/COX-2 expression and NO production in THP-1 cells, further indicating that this compound blocks inflammatory signaling and suggesting that the dichloropyridine analogues may be useful in developing P2X(7) receptor targeted anti-inflammatory agents.