4-([1,2,4]triazolo[4,3-a]quinoxalin-4-yloxy)aniline

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-([1,2,4]triazolo[4,3-a]quinoxalin-4-yloxy)aniline
• 化学式: C₁₅H₁₁N₅O
• 分子量: 277.285
• InChiKey: JJSLFMGQIHLTFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  78.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-([1,2,4]triazolo[4,3-a]quinoxalin-4-yloxy)aniline 、 邻甲苯磺酰氯 在 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 以97%的产率得到N-(4-([1,2,4]triazolo[4,3-a]quinoxalin-4-yloxy)phenyl)-2-methylbenzenesulfonamide
  参考文献：
  名称：

  Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1

  摘要：

  Urea transporter A (UT-A) isoforms encoded by the 100 Slc14a2 gene are expressed in kidney tubule epithelial cells, where they facilitate urinary concentration. UT-Al inhibition is predicted to produce a unique salt-sparing diuretic action in edema and hyponatremia. Here we report the discovery of 1,2,4-triazoloquinoxalines and the analysis of 37 synthesized analogues. The most potent compound, 8ay, containing 1,2,4triazolo[4,3-a]quinoxaline-substituted benzenesulfonamide linked by an aryl ether, rapidly and reversibly inhibited UT-Al urea transport by a noncompetitive mechanism with IC50 approximate to 150 nM; the IC50 was similar to 2 / mu M for the related urea transporter UT-B encoded by the Slc14a1 gene. Molecular modeling suggested a putative binding site on the UT-Al cytoplasmic domain. In vitro metabolism showing quinoxaline ring oxidation prompted the synthesis of metabolically stable 7,8-difluoroquinoxaline analogue 8bl, which when administered to rats produced marked diuresis and reduced urinary osmolality. 8bl has substantially improved UT-Al inhibition potency and metabolic stability compared with prior compounds.

  DOI：

  10.1021/acs.jmedchem.8b00343
• 作为产物：
  描述：

  2-氯-3-肼基喹噁啉 在 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 2.5h， 生成 4-([1,2,4]triazolo[4,3-a]quinoxalin-4-yloxy)aniline
  参考文献：
  名称：

  Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1

  摘要：

  Urea transporter A (UT-A) isoforms encoded by the 100 Slc14a2 gene are expressed in kidney tubule epithelial cells, where they facilitate urinary concentration. UT-Al inhibition is predicted to produce a unique salt-sparing diuretic action in edema and hyponatremia. Here we report the discovery of 1,2,4-triazoloquinoxalines and the analysis of 37 synthesized analogues. The most potent compound, 8ay, containing 1,2,4triazolo[4,3-a]quinoxaline-substituted benzenesulfonamide linked by an aryl ether, rapidly and reversibly inhibited UT-Al urea transport by a noncompetitive mechanism with IC50 approximate to 150 nM; the IC50 was similar to 2 / mu M for the related urea transporter UT-B encoded by the Slc14a1 gene. Molecular modeling suggested a putative binding site on the UT-Al cytoplasmic domain. In vitro metabolism showing quinoxaline ring oxidation prompted the synthesis of metabolically stable 7,8-difluoroquinoxaline analogue 8bl, which when administered to rats produced marked diuresis and reduced urinary osmolality. 8bl has substantially improved UT-Al inhibition potency and metabolic stability compared with prior compounds.

  DOI：

  10.1021/acs.jmedchem.8b00343

文献信息

• Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1
  作者：Sujin Lee、Onur Cil、Elena Diez-Cecilia、Marc O. Anderson、Alan S. Verkman

  DOI：10.1021/acs.jmedchem.8b00343

  日期：2018.4.12

  Urea transporter A (UT-A) isoforms encoded by the 100 Slc14a2 gene are expressed in kidney tubule epithelial cells, where they facilitate urinary concentration. UT-Al inhibition is predicted to produce a unique salt-sparing diuretic action in edema and hyponatremia. Here we report the discovery of 1,2,4-triazoloquinoxalines and the analysis of 37 synthesized analogues. The most potent compound, 8ay, containing 1,2,4triazolo[4,3-a]quinoxaline-substituted benzenesulfonamide linked by an aryl ether, rapidly and reversibly inhibited UT-Al urea transport by a noncompetitive mechanism with IC50 approximate to 150 nM; the IC50 was similar to 2 / mu M for the related urea transporter UT-B encoded by the Slc14a1 gene. Molecular modeling suggested a putative binding site on the UT-Al cytoplasmic domain. In vitro metabolism showing quinoxaline ring oxidation prompted the synthesis of metabolically stable 7,8-difluoroquinoxaline analogue 8bl, which when administered to rats produced marked diuresis and reduced urinary osmolality. 8bl has substantially improved UT-Al inhibition potency and metabolic stability compared with prior compounds.