VUF 5667 | 251359-78-1

• 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: VUF 5667
• 英文别名: 4-(4-Chloro-phenyl)-1-(4,4-diphenyl-butyl)-piperidin-4-ol；4-(4-chlorophenyl)-1-(4,4-diphenylbutyl)piperidin-4-ol
• CAS: 251359-78-1
• 化学式: C₂₇H₃₀ClNO
• 分子量: 419.994
• InChiKey: LLQCATMGHGFZSS-UHFFFAOYSA-N

物化性质

• 熔点：
  110.1-110.8 °C(Solv: ethyl acetate (141-78-6))
• 沸点：
  574.2±50.0 °C(Predicted)
• 密度：
  1.153±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  VUF 5667 在 盐酸 、 硫酸 作用下， 反应 72.0h， 生成
  参考文献：
  名称：

  Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28

  摘要：

  G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound I with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.06.054
• 作为产物：
  描述：

  (3-苄氧基丙基)三苯基溴化鏻 在 palladium on activated charcoal potassium tert-butylate 、 氢气 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 70.0 ℃ 、344.74 kPa 条件下， 反应 11.5h， 生成 VUF 5667
  参考文献：
  名称：

  发现新型非肽CCR1受体拮抗剂。

  摘要：

  CCR1受体的配体（MIP-1alpha和RANTES）与多种慢性炎症性疾病有关，最明显的是多发性硬化症和类风湿关节炎。由于这些配体共享一个共同的受体CCR1，因此我们寻求发现该受体的拮抗剂作为治疗这些疾病的一种方法。通过高通量筛选（HTS）已经发现了一系列新型的4-羟基哌啶，其有效抑制了MIP-1α和RANTES与重组人CCR1趋化因子受体的结合。该模板各部分的结构活性关系被描述为：最初的HTS导联1已通过合成优化为高效受体拮抗剂6s。与其他人类7-TM受体相比，该化合物对CCR1的抑制作用具有至少200倍的选择性，包括其他趋化因子受体。此外，从体外功能测定中获得的数据证明了化合物6s和与结构相关的类似物对CCR1受体的功能拮抗作用具有浓度依赖性。以化合物6s为代表的有效和选择性CCR1受体拮抗剂的发现和优化可能代表了一种治疗慢性炎性疾病的新方法。

  DOI：

  10.1021/jm990316l

文献信息

• Synthesis and Structure−Activity Relationship of the First Nonpeptidergic Inverse Agonists for the Human Cytomegalovirus Encoded Chemokine Receptor US28
  作者：Janneke W. Hulshof、Paola Casarosa、Wiro M. P. B. Menge、Leena M. S. Kuusisto、Henk van der Goot、Martine J. Smit、Iwan J. P. de Esch、Rob Leurs

  DOI：10.1021/jm050418d

  日期：2005.10.1

  US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 5-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)-2,2-diphenylpentanenitrile} as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure-activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection.