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 | 1314873-02-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 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
• 英文别名: BPO-27 (racemate)；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-carboxylic acid
• CAS: 1314873-02-3
• 化学式: C₂₆H₁₈BrN₃O₆
• 分子量: 548.349
• InChiKey: GNHIGSRGYXEQEP-UHFFFAOYSA-N

物化性质

• 沸点：
  732.9±70.0 °C(Predicted)
• 密度：
  1.68±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：6 mg/mL（10.94 mM）

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  36
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  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 在 盐酸 作用下， 以 水 、 乙酸乙酯 为溶剂， 生成 (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：

  1,3,4-三甲基尿嘧啶 在 水 、 溴 、 三氟乙酸 、 potassium hydroxide 、 zinc(II) chloride 作用下， 以 四氢呋喃 、 四氯化碳 、 乙醇 、 二氯甲烷 、 氯仿 、 氯苯 为溶剂， 反应 77.57h， 生成 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
  参考文献：
  名称：

  Potent, Metabolically Stable Benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR Inhibitors for Polycystic Kidney Disease

  摘要：

  We previously reported the discovery of pyrimido-pyrrolo-quinoxalinedione (PPQ) inhibitors of the cystic fibrosis transmentbrane conductance regulator (CFTR) chlordoide channel and showed their efficacy in an organ culture model of polycystic kidney disease (PKD) (J. Med. Chem. 2009, 52, 6447-6455). Here, we report related benzopyrimido-pyrrolo-oxazinedione (BPO) CFTR inhibitors. To establish structure activity relationships and select lead compound(s) with improved potency, metabolic stability, and aqueous solubility compared to the most potent prior compound 8 (PPQ:102, IC50 similar to 90 nM), we synthesized 16 PPQanalogues and 11 BPO analogues. The analogues were efficiently synthesized in 5-6 steps and 11-61% overall yield. Modification of 8 by bromine substitution at the 5-position of the furan ring, replacement of the secondary amine with an ether bridge, and carboxylation, gave 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 42 (BPO-27), which fully inhibited CFTR with IC50 similar to 8 nM and, compared to 8, had >10-fold greater metabolic stability and much greater polarity/aqueous solubility. In an embryonic kidney culture model of PKD, 42 prevented cyst growth with IC50 similar to 100 nM. Benzopyrimido-pyrrolo-oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD.

  DOI：

  10.1021/jm200505e

文献信息

• PYRIMIDO-PYRROLO-OXAZINE-DIONE COMPOUND INHIBITORS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR PROTEIN AND USES THEREFOR
  申请人：Verkman Alan S.

  公开号：US20140080821A1

  公开（公告）日：2014-03-20

  Provided herein are benzopyrimido-pyrrolo-oxazine-dione (BPO) compounds and pyrimido-pyrrolo-quinoxalinedione (PPQ) compounds, and compositions comprising these compounds, that inhibit cystic fibrosis transmembrane conductance regulator (CFTR) mediated ion transport and that are useful for treating diseases and disorders associated with aberrantly increased CFTR chloride channel activity, such as polycystic kidney disease and secretory diarrheas. The compounds and compositions comprising the compounds described herein may be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.

  本文提供了苯并嘧啶基吡咯氧噻吩二酮（BPO）化合物和嘧啶基吡咯喹啉二酮（PPQ）化合物以及含有这些化合物的组合物，其抑制囊性纤维化跨膜传导调节因子（CFTR）介导的离子传输，并且可用于治疗与CFTR氯通道活性异常增加相关的疾病和障碍，例如多囊肾病和分泌性腹泻。本文所描述的化合物和组合物可用于抑制在患有多囊肾病的人中囊肿的扩张或预防囊肿的形成。
• Rapid quantitative assay to measure CFTR function in a primary intestinal culture model
  申请人：UMC Utrecht Holding B.V.

  公开号：US10006904B2

  公开（公告）日：2018-06-26

  The invention relates to an assay for diagnosing a disease or affliction that affects fluid uptake or secretion or for studying the effectiveness of one or more drugs for treating the disease or affliction, wherein the assay comprises measuring swelling of one or more organoids.

  本发明涉及一种检测方法，用于诊断影响液体吸收或分泌的疾病或痛苦，或研究一种或多种治疗疾病或痛苦的药物的有效性，其中检测方法包括测量一种或多种有机体的肿胀。
• Methods to decrease susceptibility to asthmatic bronchoconstriction
  申请人：Cornell University

  公开号：US10159678B2

  公开（公告）日：2018-12-25

  Methods and compositions are described for reducing airway reactivity and the susceptibility to asthmatic bronchoconstriction that involve increasing sphingolipid content in airways and lungs of a mammalian subject.

  本文描述了降低气道反应性和哮喘性支气管收缩易感性的方法和组合物，包括增加哺乳动物气道和肺中的鞘脂含量。
• RAPID QUANTITATIVE ASSAY TO MEASURE CFTR FUNCTION IN A PRIMARY INTESTINAL CULTURE MODEL
  申请人：UMC Utrecht Holding B.V.

  公开号：US20150011420A1

  公开（公告）日：2015-01-08

  The invention relates to an assay for diagnosing a disease or affliction that affects fluid uptake or secretion or for studying the effectiveness of one or more drugs for treating the disease or affliction, wherein the assay comprises measuring swelling of one or more organoids.
• METHODS TO DECREASE SUSCEPTIBILITY TO ASTHMATIC BRONCHOCONSTRICTION
  申请人：Cornell University

  公开号：US20150139915A1

  公开（公告）日：2015-05-21

  Methods and compositions are described for reducing airway reactivity and the susceptibility to asthmatic bronchoconstriction that involve increasing sphingolipid content in airways and lungs of a mammalian subject.