(9S)-9-(5-bromofuran-2-yl)-12,14-dimethyl-13,15-dioxo-17-phenyl-8-oxa-1,12,14-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-2(7),3,5,10,16-pentaene-4-carboxylate;propan-2-ylazanium | 1429420-23-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (9S)-9-(5-bromofuran-2-yl)-12,14-dimethyl-13,15-dioxo-17-phenyl-8-oxa-1,12,14-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-2(7),3,5,10,16-pentaene-4-carboxylate;propan-2-ylazanium
• CAS: 1429420-23-4
• 化学式: C₃H₉N*C₂₆H₁₈BrN₃O₆
• 分子量: 607.461
• InChiKey: TZNBGWXBTYKWOD-GNAFDRTKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.58
• 重原子数：
  40
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (9S)-9-(5-bromofuran-2-yl)-12,14-dimethyl-13,15-dioxo-17-phenyl-8-oxa-1,12,14-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-2(7),3,5,10,16-pentaene-4-carboxylate;propan-2-ylazanium 在 盐酸 作用下， 以 水 、 乙酸乙酯 为溶剂， 以89%的产率得到(S)-BPO-27
  参考文献：
  名称：

  Absolute Configuration and Biological Properties of Enantiomers of CFTR Inhibitor BPO-27

  摘要：

  We previously reported benzopyrimido-pyrrolo-oxazine-dione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27 (1), which contains a single chiral center, and determined their absolute configuration, activity, and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by X-ray crystallography, inhibited CFTR chloride conductance with IC50 approximate to 4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5% metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1 decayed with t(1/2) approximate to 1.6 h and gave sustained therapeutic concentrations in kidney.

  DOI：

  10.1021/ml400069k
• 作为产物：
  描述：

  6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4',5':3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylic acid 、 异丙胺 在 preparative-scale chiral SFC 作用下， 以71.5%的产率得到(9S)-9-(5-bromofuran-2-yl)-12,14-dimethyl-13,15-dioxo-17-phenyl-8-oxa-1,12,14-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-2(7),3,5,10,16-pentaene-4-carboxylate;propan-2-ylazanium
  参考文献：
  名称：

  Absolute Configuration and Biological Properties of Enantiomers of CFTR Inhibitor BPO-27

  摘要：

  We previously reported benzopyrimido-pyrrolo-oxazine-dione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27 (1), which contains a single chiral center, and determined their absolute configuration, activity, and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by X-ray crystallography, inhibited CFTR chloride conductance with IC50 approximate to 4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5% metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1 decayed with t(1/2) approximate to 1.6 h and gave sustained therapeutic concentrations in kidney.

  DOI：

  10.1021/ml400069k

文献信息

• Absolute Configuration and Biological Properties of Enantiomers of CFTR Inhibitor BPO-27
  作者：David S. Snyder、Lukmanee Tradtrantip、Sailaja Battula、Chenjuan Yao、Puay-wah Phuan、James C. Fettinger、Mark J. Kurth、A. S. Verkman

  DOI：10.1021/ml400069k

  日期：2013.5.9

  We previously reported benzopyrimido-pyrrolo-oxazine-dione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27 (1), which contains a single chiral center, and determined their absolute configuration, activity, and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by X-ray crystallography, inhibited CFTR chloride conductance with IC50 approximate to 4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5% metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1 decayed with t(1/2) approximate to 1.6 h and gave sustained therapeutic concentrations in kidney.