trans-N-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}(4-{[(phenylmethoxy)carbonylamino]methyl}cyclohexyl)carboxamide | 519058-32-3

• 英文名称: trans-N-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}(4-{[(phenylmethoxy)carbonylamino]methyl}cyclohexyl)carboxamide
• CAS: 519058-32-3
• 化学式: C₂₅H₂₇F₃N₂O₄
• 分子量: 476.496
• InChiKey: DIYPBFZADKTCPO-UAPYVXQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.74
• 重原子数：
  34.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  84.5
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  trans-N-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}(4-{[(phenylmethoxy)carbonylamino]methyl}cyclohexyl)carboxamide 在 palladium on activated charcoal ammonium acetate 、 氢气 、 溶剂黄146 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、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
• 作为产物：
  描述：

  trans-4-{[(phenylmethoxy)carbonylamino]methyl}cyclohexanecarboxylic acid 、 2-氨基-1-(3-三氟甲基苯基)乙酮盐酸盐 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 trans-N-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}(4-{[(phenylmethoxy)carbonylamino]methyl}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

• 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