2-methyl-4-(4-methylpiperazin-1-yl)-6-phenylpyrimidine | 1605301-41-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2-methyl-4-(4-methylpiperazin-1-yl)-6-phenylpyrimidine
• 英文别名: VUF14481
• CAS: 1605301-41-4
• 化学式: C₁₆H₂₀N₄
• 分子量: 268.362
• InChiKey: FHEMZKQJVJEDAZ-UHFFFAOYSA-N

物化性质

• 沸点：
  438.4±45.0 °C(Predicted)
• 密度：
  1.114±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  32.26
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  2-chloro-4-(4'-methylpiperazin-1'-yl)-6-phenylpyrimidine 、 三甲基环三硼氧烷 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 caesium carbonate 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 水 为溶剂， 反应 16.0h， 以54%的产率得到2-methyl-4-(4-methylpiperazin-1-yl)-6-phenylpyrimidine
  参考文献：
  名称：

  Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98^3.36of the human histamine H₄receptor

  摘要：

  Background and PurposeThe recently proposed binding mode of 2‐aminopyrimidines to the human (h) histamine H4 receptor suggests that the 2‐amino group of these ligands interacts with glutamic acid residue E1825.46 in the transmembrane (TM) helix 5 of this receptor. Interestingly, substituents at the 2‐position of this pyrimidine are also in close proximity to the cysteine residue C983.36 in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C983.36 by functioning as a Michael acceptor. A covalent pyrimidine analogue will not only prove this proposed binding mode, but will also provide a valuable tool for H4 receptor research.Experimental ApproachWe designed and synthesized VUF14480, and pharmacologically characterized this compound in hH4 receptor radioligand binding, G protein activation and β‐arrestin2 recruitment experiments. The ability of VUF14480 to act as a covalent binder was assessed both chemically and pharmacologically.Key ResultsVUF14480 was shown to be a partial agonist of hH4 receptor‐mediated G protein signalling and β‐arrestin2 recruitment. VUF14480 bound covalently to the hH4 receptor with submicromolar affinity. Serine substitution of C983.36 prevented this covalent interaction.Conclusion and ImplicationsVUF14480 is thought to bind covalently to the hH4 receptor‐C983.36 residue and partially induce hH4 receptor‐mediated G protein activation and β‐arrestin2 recruitment. Moreover, these observations confirm our previously proposed binding mode of 2‐aminopyrimidines. VUF14480 will be a useful tool to stabilize the receptor into an active confirmation and further investigate the structure of the active hH4 receptor.Linked ArticlesThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/ 10.1111/bph.2013.170.issue‐1

  DOI：

  10.1111/bph.12113