4-oxo-carbazeran | 96724-43-5

• 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: 4-oxo-carbazeran
• 英文别名: 4-Hydroxycarbazeran；[1-(6,7-dimethoxy-4-oxo-3H-phthalazin-1-yl)piperidin-4-yl] N-ethylcarbamate
• CAS: 96724-43-5
• 化学式: C₁₈H₂₄N₄O₅
• 分子量: 376.412
• InChiKey: YIFOKLMSOFKZBP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  卡巴折伦 在 aldehyde oxidase 作用下， 生成 4-oxo-carbazeran
  参考文献：
  名称：

  肝外醛氧化酶活性对人体清除的贡献

  摘要：

  醛氧化酶 (AOX) 是一种可溶性胞质酶，可代谢多种N-杂环化合物和有机醛。它具有广泛的组织分布，在肝、肾和肺中含量最高。通过对分离的肝脏部分（胞质溶胶，S9）甚至肝细胞进行体外评估，对 AOX 底物的人体清除率预测在很大程度上低估了临床结果。关于为什么会出现这种情况，人们提出了各种假设。一种解释是肝外 AOX 表达对 AOX 清除有可衡量的贡献，并且至少部分地导致经常观察到的预测不足。虽然 AOX 表达已在几个肝外组织中得到证实，但其中的活性和对整体人体清除的潜在贡献尚未得到彻底研究。在这项工作中，使用选定的肝外人体组织（肾、肺、脉管系统和肠）使用卡巴泽兰作为探针底物进行测量。使用最佳可用参数将测量的活动缩放到全身清除率，并与肝脏 S9 分数进行比较。在这里，从肾脏、肺、脉管系统和肠道获得的综合 AOX 清除率非常低，小于肝脏的 1%。这项工作表明，来自肝外来源的 AOX 代谢在人类活动

  DOI：

  10.1124/dmd.120.000313

文献信息

• A rapid and specific derivatization procedure to identify acyl-glucuronides by mass spectrometry
  作者：Alfin D. N. Vaz、Wei Wei Wang、Andrew J. Bessire、Raman Sharma、Anne E. Hagen

  DOI：10.1002/rcm.4621

  日期：2010.7.30

  A simple procedure is described to identify acyl‐glucuronides by coupled liquid chromatography/mass spectrometry after derivatization to a hydroxamic acid with hydroxylamine. The reaction specificity obviates the need for isolation of the acyl‐glucuronide from an extract. Glucuronides derived from carbamic acids, and alkyl‐ and aromatic amines, are inert to the derivatization reaction conditions, making

  描述了一种简单的程序，用羟胺衍生为异羟肟酸后，通过液相色谱/质谱联用鉴定酰基葡萄糖醛酸。反应特异性消除了从提取物中分离酰基葡糖醛酸苷的需要。衍生自氨基甲酸，烷基胺和芳族胺的葡糖苷酸对衍生化反应条件呈惰性，使异羟肟酸衍生物成为酰基葡糖醛酸苷的指纹图谱。版权所有©2010 John Wiley＆Sons，Ltd.
• Evaluation of Carbazeran 4-Oxidation and <i>O</i>⁶-Benzylguanine 8-Oxidation as Catalytic Markers of Human Aldehyde Oxidase: Impact of Cytosolic Contamination of Liver Microsomes
  作者：Jiarong Xie、Nur Fazilah Saburulla、Shiyan Chen、Siew Ying Wong、Ze Ping Yap、Linghua Harris Zhang、Aik Jiang Lau

  DOI：10.1124/dmd.118.082099

  日期：2019.1

  The present study investigated the contribution of microsomal cytochrome P450 and cytosolic aldehyde oxidase-1 (AOX-1) to carbazeran 4-oxidation and O 6-benzylguanine 8-oxidation in human liver microsomal, cytosolic, and S9 fractions. Incubations containing carbazeran and human liver microsomes with or without exogenously added NADPH yielded comparable levels of 4-oxo-carbazeran. O 6-Benzylguanine 8-oxidation occurred in microsomal incubations, and the extent was increased by NADPH. Human recombinant CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 did not catalyze carbazeran 4-oxidation, whereas CYP1A2 was highly active in O 6-benzylguanine 8-oxidation. 1-Aminobenzotriazole, a pan-cytochrome P450 inhibitor, decreased O 6-benzylguanine 8-oxidation, but not carbazeran 4-oxidation, in microsomal incubations, whereas 1-aminobenzotriazole and furafylline (a CYP1A2-selective inhibitor) did not inhibit carbazeran 4-oxidation or O 6-benzylguanine 8-oxidation in human liver S9 fraction. Carbazeran 4-oxidation in incubations containing human liver microsomes (from multiple donors and commercial suppliers) was attributed to microsomal preparations contaminated with AOX-1, as suggested by liver microsomal experiments indicating a decrease in carbazeran 4-oxidation by an AOX-1 inhibitor (hydralazine), and to detection of AOX-1 protein (at one-third the level of that in liver cytosol). Cytosolic contamination of liver microsomes was further demonstrated by the formation of dehydroepiandrosterone sulfate (catalyzed by cytosolic sulfotransferases) in liver microsomal incubations containing dehydroepiandrosterone. In conclusion, carbazeran 4-oxidation and O 6-benzylguanine 8-oxidation are enzyme-selective catalytic markers of human AOX-1, as shown in human liver S9 fraction expressing cytochrome P450 and AOX-1. This study highlights the negative impact of cytosolic contamination of liver microsomes on the interpretation of reaction phenotyping data collected in an in vitro study performed in microsomal fractions.

  hydro气化器。
• Biotransformation of carbazeran in guinea pig: Effect of hydralazine pretreatment
  作者：D. J. P. Critchley、D. J. Rance、C. Beedham

  DOI：10.3109/00498259409043219

  日期：1994.1

  1. After administration of [C-14]-carbazeran by oral gavage to guinea pigs, 48% of the dosed radioactivity was recovered in urine and 46% in faeces after 144h. 2. The major urinary metabolite was identified by infrared spectroscopy and mass spectrometry as the O-glucuronide of O-desmethyl-4-oxocarbazeran, O-demethylation having taken place at the 6- or 7-position. The corresponding aglycone was identified as the major faecal metabolite. 3. A minor metabolite in urine was identified as the 4-oxo-4'-hydroxy derivative of carbazeran. 4. In animals pretreated with hydralazine, an aldehyde oxidase inhibitor, less radioactivity was extracted in the urine and a significant decrease was observed in the levels of the major urinary metabolite. 5. These results show that aldehyde oxidase plays a key role in the metabolism of carbazeran in guinea pig as it does in man. The similarity of man and guinea pig liver aldehyde oxidase has been observed previously in vitro.
• Dissecting Parameters Contributing to the Underprediction of Aldehyde Oxidase-Mediated Metabolic Clearance of Drugs
  作者：Sandhya Subash、Dilip K. Singh、Deepak S. Ahire、S. Cyrus Khojasteh、Bernard P. Murray、Michael A. Zientek、Robert S. Jones、Priyanka Kulkarni、Bill J. Smith、Scott Heyward、Ciarán N. Cronin、Bhagwat Prasad

  DOI：10.1124/dmd.123.001379

  日期：2023.10
• Contribution of Extrahepatic Aldehyde Oxidase Activity to Human Clearance
  作者：Kirk D. Kozminski、Jangir Selimkhanov、Scott Heyward、Michael A. Zientek

  DOI：10.1124/dmd.120.000313

  日期：2021.9

  Aldehyde oxidase (AOX) is a soluble, cytosolic enzyme that metabolizes various N-heterocyclic compounds and organic aldehydes. It has wide tissue distribution with highest levels found in liver, kidney, and lung. Human clearance projections of AOX substrates by in vitro assessments in isolated liver fractions (cytosol, S9) and even hepatocytes have been largely underpredictive of clinical outcomes

  醛氧化酶 (AOX) 是一种可溶性胞质酶，可代谢多种N-杂环化合物和有机醛。它具有广泛的组织分布，在肝、肾和肺中含量最高。通过对分离的肝脏部分（胞质溶胶，S9）甚至肝细胞进行体外评估，对 AOX 底物的人体清除率预测在很大程度上低估了临床结果。关于为什么会出现这种情况，人们提出了各种假设。一种解释是肝外 AOX 表达对 AOX 清除有可衡量的贡献，并且至少部分地导致经常观察到的预测不足。虽然 AOX 表达已在几个肝外组织中得到证实，但其中的活性和对整体人体清除的潜在贡献尚未得到彻底研究。在这项工作中，使用选定的肝外人体组织（肾、肺、脉管系统和肠）使用卡巴泽兰作为探针底物进行测量。使用最佳可用参数将测量的活动缩放到全身清除率，并与肝脏 S9 分数进行比较。在这里，从肾脏、肺、脉管系统和肠道获得的综合 AOX 清除率非常低，小于肝脏的 1%。这项工作表明，来自肝外来源的 AOX 代谢在人类活动