N-(2-hydroxypropyl)(4-[4-(3-bromophenyl)imidazol-2-yl]cyclohexyl)carboxamide | 871502-09-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(2-hydroxypropyl)(4-[4-(3-bromophenyl)imidazol-2-yl]cyclohexyl)carboxamide
• CAS: 871502-09-9
• 化学式: C₁₉H₂₄BrN₃O₂
• 分子量: 406.322
• InChiKey: ZIAYKXKPJCRQKD-KAOCOCSGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.61
• 重原子数：
  25.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  78.01
• 氢给体数：
  3.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  N-(2-hydroxypropyl)(4-[4-(3-bromophenyl)imidazol-2-yl]cyclohexyl)carboxamide 在 草酰氯 、 TEA 、 二甲基亚砜 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Substituted 2-Cyclohexyl-4-phenyl-1H-imidazoles:  Potent and Selective Neuropeptide Y Y5-Receptor Antagonists

  摘要：

  Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series of small molecule Y5 antagonists derived from a 2,4diaryl-1H-imidazole lead. The main objectives of our structural optimization efforts were to produce novel and potent Y5 antagonists with an improved oral pharmacokinetic profile and less affinity for the hERG potassium channel compared to the lead 2,4-diarylimidazole structures. These goals were accomplished by replacement of the 2-aryl ring with a cyclohexyl ring and subsequent elaboration of the 4-position of the cyclohexyl ring with a variety of hydrophilic functionalities. The resulting compound, N-(2-hydroxy-tert-butyl)(4-{4-[3-(trifluoro-methyl)phenyl]imidazol-2-yl}cyclohexyl)carboxamide (20), displayed good potency at the Y5 receptor (K-i = 3 nM), while interactions at the hERG channel were essentially eliminated (6% inhibition at a concentration of 3 muM). Importantly, the pharmacokinetic properties of 20 (F = 36%) represented a marked improvement over that of the initial 2,4-diarylimidazole structures.

  DOI：

  10.1021/jm030490g
• 作为产物：
  描述：

  trans-methyl 4-[4-(3-bromophenyl)imidazol-2-yl]cyclohexanecarboxylate 在 lithium hydroxide 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-(2-hydroxypropyl)(4-[4-(3-bromophenyl)imidazol-2-yl]cyclohexyl)carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Substituted 2-Cyclohexyl-4-phenyl-1H-imidazoles:  Potent and Selective Neuropeptide Y Y5-Receptor Antagonists

  摘要：

  Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series of small molecule Y5 antagonists derived from a 2,4diaryl-1H-imidazole lead. The main objectives of our structural optimization efforts were to produce novel and potent Y5 antagonists with an improved oral pharmacokinetic profile and less affinity for the hERG potassium channel compared to the lead 2,4-diarylimidazole structures. These goals were accomplished by replacement of the 2-aryl ring with a cyclohexyl ring and subsequent elaboration of the 4-position of the cyclohexyl ring with a variety of hydrophilic functionalities. The resulting compound, N-(2-hydroxy-tert-butyl)(4-{4-[3-(trifluoro-methyl)phenyl]imidazol-2-yl}cyclohexyl)carboxamide (20), displayed good potency at the Y5 receptor (K-i = 3 nM), while interactions at the hERG channel were essentially eliminated (6% inhibition at a concentration of 3 muM). Importantly, the pharmacokinetic properties of 20 (F = 36%) represented a marked improvement over that of the initial 2,4-diarylimidazole structures.

  DOI：

  10.1021/jm030490g

文献信息

• Substituted 2-cyclohexyl-4-phenyl-1H-imidazole derivatives
  申请人：NEUROGEN CORPORATION

  公开号：US20030144290A1

  公开（公告）日：2003-07-31

  Substituted 2-cyclohexyl-4-phenyl-1H-imidazole derivatives capable of modulating NPY5 receptor activity, are provided. Such compounds may be used to modulate NPY binding to NPY5 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of disorders (e.g., eating disorders such as obesity or bulimia, psychiatric disorders, diabetes and cardiovascular disorders such as hypertension) in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such compounds for detecting NPY5 receptors.

  提供了能够调节NPY5受体活性的取代2-环己基-4-苯基-1H-咪唑衍生物。这些化合物可以用于体内或体外调节NPY结合到NPY5受体，并且在治疗各种疾病（例如，饮食失调，如肥胖症或贪食症，精神障碍，糖尿病和心血管疾病，如高血压）的人类，家养伴侣动物和家畜动物中特别有用。提供了用于治疗此类疾病的药物组合物和方法，以及用于检测NPY5受体的方法。
• 2-Cyclohexyl-4-phenyl-1H-imidazole derivatives as ligands for the neuropeptide Y5 receptor
  申请人：NEUROGEN CORPORATION

  公开号：EP1306085B1

  公开（公告）日：2007-02-14