4-((2,4-dioxo-6-(4-(2-phenylacetyl)piperazin-1-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phenyl isoquinoline-5-sulfonate

• 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: 4-((2,4-dioxo-6-(4-(2-phenylacetyl)piperazin-1-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phenyl isoquinoline-5-sulfonate
• 英文别名: 4-((2,4-dioxo-6-(4-(2-phenylacetyl)piperazin-1-yl)-3,4-dihydropyrimidine-1-(2H)-yl)methyl)phenyl isoquinoline-5-sulfonate；[4-[[2,4-Dioxo-6-[4-(2-phenylacetyl)piperazin-1-yl]pyrimidin-1-yl]methyl]phenyl] isoquinoline-5-sulfonate；[4-[[2,4-dioxo-6-[4-(2-phenylacetyl)piperazin-1-yl]pyrimidin-1-yl]methyl]phenyl] isoquinoline-5-sulfonate
• 化学式: C₃₂H₂₉N₅O₆S
• 分子量: 611.678
• InChiKey: GXUDYHKLJVYFBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  138
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (4-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane 在 哌啶 、 sodium hydride 、 碳酸氢钠 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 乙酰氯 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.5h， 生成 4-((2,4-dioxo-6-(4-(2-phenylacetyl)piperazin-1-yl)-3,4-dihydropyrimidin-1(2H)-yl)methyl)phenyl isoquinoline-5-sulfonate
  参考文献：
  名称：

  Structure–activity relationship studies of pyrimidine-2,4-dione derivatives as potent P2X7 receptor antagonists

  摘要：

  As an optimization strategy, the flexible structure of KN-62, a known P2X(7) receptor antagonist, was converted into conformationally constrained derivatives using pyrimidine-2,4-dione as the core skeleton. Various modifications at the 4-position of the piperazine moiety of the new lead compound were performed to improve P2X(7) receptor antagonistic activities, which were evaluated in HEK293 cells stably expressing the human P2X(7) receptor (EtBr uptake assay) and in THP-1 cells (IL-1 beta ELISA assay). According to the results, polycycloalkyl acyl or di-halogenated benzoyl substituents were Much more favorable than the original phenyl group of KN-62. Among these compounds, the trifluoromethyl-chloro benzoyl derivative 18m and adamantyl carbonyl derivatives 19g-19i and 19k showed potent antagonistic effects, with IC50 values ranging from 10 to 30 nM. In addition, the in vitro adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of 18m was determined to be in acceptable ranges in terms of metabolic stability and cytotoxicity. These results suggest that pyrimidine-2,4-dione derivatives may be promising novel P2X(7) receptor antagonists for the development of anti-inflammatory drugs. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.036

文献信息

• Structure–activity relationship studies of pyrimidine-2,4-dione derivatives as potent P2X7 receptor antagonists
  作者：Jin-Hee Park、Ga-Eun Lee、So-Deok Lee、Hyojin Ko、Yong-Chul Kim

  DOI：10.1016/j.ejmech.2015.10.036

  日期：2015.12

  As an optimization strategy, the flexible structure of KN-62, a known P2X(7) receptor antagonist, was converted into conformationally constrained derivatives using pyrimidine-2,4-dione as the core skeleton. Various modifications at the 4-position of the piperazine moiety of the new lead compound were performed to improve P2X(7) receptor antagonistic activities, which were evaluated in HEK293 cells stably expressing the human P2X(7) receptor (EtBr uptake assay) and in THP-1 cells (IL-1 beta ELISA assay). According to the results, polycycloalkyl acyl or di-halogenated benzoyl substituents were Much more favorable than the original phenyl group of KN-62. Among these compounds, the trifluoromethyl-chloro benzoyl derivative 18m and adamantyl carbonyl derivatives 19g-19i and 19k showed potent antagonistic effects, with IC50 values ranging from 10 to 30 nM. In addition, the in vitro adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of 18m was determined to be in acceptable ranges in terms of metabolic stability and cytotoxicity. These results suggest that pyrimidine-2,4-dione derivatives may be promising novel P2X(7) receptor antagonists for the development of anti-inflammatory drugs. (C) 2015 Elsevier Masson SAS. All rights reserved.