4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-1-methyl-1H-pyrazol-5-yl)-2-methylbenzamide | 1358573-38-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-1-methyl-1H-pyrazol-5-yl)-2-methylbenzamide
• 英文别名: 4-[5-[[3-Fluoro-5-(trifluoromethyl)phenyl]methyl]-2-methylpyrazol-3-yl]-2-methylbenzamide
• CAS: 1358573-38-2
• 化学式: C₂₀H₁₇F₄N₃O
• 分子量: 391.368
• InChiKey: DIWBGPZKWMTJDG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  60.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-氟-5-(三氟甲基)苯乙酸 在 吡啶 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 1-羟基-1H-苯并三唑铵盐 、 sodium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 、 乙二醇二甲醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-1-methyl-1H-pyrazol-5-yl)-2-methylbenzamide
  参考文献：
  名称：

  Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists

  摘要：

  G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzy1)-5-methyl-1H-1,2,4-triazol-1-y1)-2-methylbenzamide (4u; half maximal effective concentration (EC50) = 75 nM, maximal response (E-max) = 122%) starting from a high-throughput screening hit 3 (EC50 = 470 nM, E-max = 56%). The structural features of a reported GPR52 agonist were applied to 3, led to design 4-azolylbenzamides as novel GPR52 agonists. A structure-activity relationship study of 4-azolylbenzamide resulted in the design of the 1,2,4-triazole derivative 4u, which demonstrated excellent bioavailability in rats (F = 53.8%). Oral administration of 4u (10 mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.03.064

文献信息

• Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists
  作者：Kazuyuki Tokumaru、Yoshiteru Ito、Izumi Nomura、Takashi Nakahata、Yuji Shimizu、Emi Kurimoto、Kazunobu Aoyama、Kazuyoshi Aso

  DOI：10.1016/j.bmc.2017.03.064

  日期：2017.6

  G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzy1)-5-methyl-1H-1,2,4-triazol-1-y1)-2-methylbenzamide (4u; half maximal effective concentration (EC50) = 75 nM, maximal response (E-max) = 122%) starting from a high-throughput screening hit 3 (EC50 = 470 nM, E-max = 56%). The structural features of a reported GPR52 agonist were applied to 3, led to design 4-azolylbenzamides as novel GPR52 agonists. A structure-activity relationship study of 4-azolylbenzamide resulted in the design of the 1,2,4-triazole derivative 4u, which demonstrated excellent bioavailability in rats (F = 53.8%). Oral administration of 4u (10 mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists. (C) 2017 Elsevier Ltd. All rights reserved.