N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-benzenesulfonamide | 519058-41-4

• 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-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-benzenesulfonamide
• CAS: 519058-41-4
• 化学式: C₂₃H₂₄F₃N₃O₂S
• 分子量: 463.524
• InChiKey: NVHUYUFYASVZKR-QAQDUYKDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.35
• 重原子数：
  32.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  74.85
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-benzenesulfonamide 、 碘甲烷 在 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 0.08h， 以40%的产率得到N-Methyl-N-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-benzenesulfonamide
  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：

  2-氨基-1-(3-三氟甲基苯基)乙酮盐酸盐 在 palladium on activated charcoal ammonium acetate 、 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 溶剂黄146 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 20.0~80.0 ℃ 、379.21 kPa 条件下， 反应 18.0h， 生成 N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-benzenesulfonamide
  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

• Design, Synthesis, and Biological Evaluation of Substituted 2-Cyclohexyl-4-phenyl-1<i>H</i>-imidazoles:  Potent and Selective Neuropeptide Y Y5-Receptor Antagonists
  作者：Charles A. Blum、Xiaozhang Zheng、Stéphane De Lombaert

  DOI：10.1021/jm030490g

  日期：2004.4.1

  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.