N-(2-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)phenyl)-5-methylfuran-2-carboxamide | 1192478-29-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-(2-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)phenyl)-5-methylfuran-2-carboxamide
• 英文别名: 12,14-Dimethyl-9-(5-methylfuran-2-yl)-17-phenyl-1,8,12,14-tetrazatetracyclo[8.7.0.02,7.011,16]heptadeca-2,4,6,8,10,16-hexaene-13,15-dione
• CAS: 1192478-29-7
• 化学式: C₂₆H₂₀N₄O₃
• 分子量: 436.47
• InChiKey: RSBJYRGOYAIVBG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  33
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  71.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6,7-二氢-7,9-二甲基-6-(5-甲基-2-呋喃基)-11-苯基嘧啶并[4',5':3,4]吡咯并[1,2-a]喹喔啉-8,10(5H,9)-二酮 在 potassium permanganate 作用下， 以 丙酮 为溶剂， 以40%的产率得到N-(2-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)phenyl)-5-methylfuran-2-carboxamide
  参考文献：
  名称：

  Nanomolar Potency Pyrimido-pyrrolo-quinoxalinedione CFTR Inhibitor Reduces Cyst Size in a Polycystic Kidney Disease Model

  摘要：

  Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride, channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of similar to 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347. analogues established structure-activity relationships. The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4',5'-3,4]pyrrolo[ 1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC50 similar to 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal-kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date.

  DOI：

  10.1021/jm9009873

文献信息

• Nanomolar Potency Pyrimido-pyrrolo-quinoxalinedione CFTR Inhibitor Reduces Cyst Size in a Polycystic Kidney Disease Model
  作者：Lukmanee Tradtrantip、N. D. Sonawane、Wan Namkung、A. S. Verkman

  DOI：10.1021/jm9009873

  日期：2009.10.22

  Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride, channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of similar to 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347. analogues established structure-activity relationships. The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4',5'-3,4]pyrrolo[ 1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC50 similar to 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal-kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date.