4-(4-(2-aminophenoxy)phenyl)-N-(4-methoxyphenyl)pyrimidin-2-amine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-(4-(2-aminophenoxy)phenyl)-N-(4-methoxyphenyl)pyrimidin-2-amine
• 英文别名: 4-[4-(2-aminophenoxy)phenyl]-N-(4-methoxyphenyl)pyrimidin-2-amine
• 化学式: C₂₃H₂₀N₄O₂
• 分子量: 384.437
• InChiKey: BFXVEZYWDOPAMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  82.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-羟基苯硼酸频哪醇酯 在 盐酸 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 铁粉 、 sodium carbonate 、 氯化铵 作用下， 以 乙醇 、 水 、 二甲基亚砜 、 甲苯 为溶剂， 反应 6.0h， 生成 4-(4-(2-aminophenoxy)phenyl)-N-(4-methoxyphenyl)pyrimidin-2-amine
  参考文献：
  名称：

  具有强抗炎作用的基于氨基嘧啶的IκB激酶β抑制剂的优化和生物学评价

  摘要：

  靶向IκB激酶β（IKKβ）在炎症性疾病的治疗方法开发中可能是一个有前途的策略，因为IKKβ被公认为是NF-κB信号传导途径的关键介体。在这项研究中，我们已经通过基于结构的设计策略成功开发了基于氨基嘧啶的IKKβ抑制剂的结构-活性关系（SAR）谱，以改善抗炎作用的理化特性和细胞活性。代表性化合物通过抑制诱导型一氧化氮合酶（iNOS）的合成，在减少一氧化氮（NO）方面显示出所需的活性，并强烈抑制促炎性细胞因子（IL-1α，IL-6和TNF-α）的表达。8e的抑制作用 NF-κB途径的磷酸化作用进一步证实，NF-κB信号通路的抑制诱导了LPS刺激的Raw 264.7细胞的抗炎作用。

  DOI：

  10.1016/j.ejmech.2016.07.075

文献信息

• Computational Design and Discovery of Nanomolar Inhibitors of IκB Kinase β
  作者：Hwangseo Park、Yongje Shin、Hyeonjeong Choe、Sungwoo Hong

  DOI：10.1021/ja510636t

  日期：2015.1.14

  IkB kinase beta (IKK beta) is a useful target for the discovery of new medicines for cancer and inflammatory diseases. In this study, we aimed to identify new classes of potent IKK beta inhibitors based on structure-based virtual screening, de novo design, and chemical synthesis. To increase the probability of finding actual inhibitors, we improved the scoring function for the estimation of the IKK beta-inhibitor binding affinity by introducing proper solvation free energy and conformational destabilization energy terms for putative inhibitors. Using this modified scoring function, we have been able to identify 15 submicromolar-level IKK beta inhibitors that possess the phenyl-(4-phenyl-pyrimidin-2-yl)-amine moiety as the molecular core. Decomposition analysis of the calculated binding free energies showed that a high biochemical potency could be achieved by lowering the desolvation cost and the conformational destabilization for the inhibitor required for binding to IKK beta as well as by strengthening the interactions in the ATP-binding site. The formation of two hydrogen bonds with backbone amide groups of Cys99 in the hinge region was found to be necessary for tight binding of the inhibitors in the ATP-binding site. From molecular dynamics simulations of IKK beta-inhibitor complexes, we also found that complete dynamic stability of the bidentate hydrogen bond with Cys99 was required for low nanomolar-level inhibitory activity. This implies that the scoring function for virtual screening and de novo design would be further optimized by introducing an additional energy term to measure the dynamic stability of the key interactions in enzymeinhibitor complexes.