乙酰胺,N-[3-(3-氰基-4,5-二氢-5-羰基吡唑并[1,5-a]嘧啶-7-基)苯基]-N-乙基- | 159225-99-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 乙酰胺,N-[3-(3-氰基-4,5-二氢-5-羰基吡唑并[1,5-a]嘧啶-7-基)苯基]-N-乙基-
• 英文名称: 5-oxo-Zaleplon
• 英文别名: 5-Oxozaleplon；N-[3-(3-cyano-5-oxo-4H-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide
• CAS: 159225-99-7
• 化学式: C₁₇H₁₅N₅O₂
• 分子量: 321.338
• InChiKey: LUFPEMFJYAYYDI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  91
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  乙酰胺,N-[3-(3-氰基-4,5-二氢-5-羰基吡唑并[1,5-a]嘧啶-7-基)苯基]-N-乙基- 在 cytochrome P₄₅₀ human liver microsomes 作用下， 以 phosphate buffer 为溶剂， 反应 0.5h， 生成 乙酰胺,N-[3-(3-氰基-4,5-二氢-5-羰基吡唑并[1,5-a]嘧啶-7-基)苯基]-
  参考文献：
  名称：

  Metabolism of Zaleplon by human hepatic microsomal cytochrome P450 isoforms

  摘要：

  1. The metabolism of Zaleplon (CL-284,846; ZAL) has been studied in human liver microsomal preparations and in cDNA-expressed human cytochrome P450 (CYP) isoforms.2. Human liver microsomes catalysed the NADPH-dependent N-deethylation of ZAL to DZAL (CL-284,859), but not to two other known in vivo metabolites, namely M1 (CL-345,644) and M2 (CL-345,905). Sigmoidal kinetic plots were observed for ZAL deethylation indicating positive cooperativity.3. The metabolism of ZAL to DZAL was determined in a characterized bank of 24 human liver microsomal preparations. Good correlations (r(2) = 0.734-0.937) were observed with caffeine 8-hydroxylase, diazepam 3-hydroxylase, dextromethorphan N-demethylase and testosterone 2 beta-, 6 beta- and 15 beta-hydroxylase activities, which are all catalysed by CYP3A isoforms. In contrast, poor correlations (r(2) = 0.152-0.428) were observed for enzymatic markers for CYP1A2, CYP2A6, CYP2C9/10, CYP2D6, CYP2E1 and CYP4A9/11.4. The metabolism of ZAL to DZAL in human liver microsomes was inhibited to 6-15 % of control by 5-50 mu M of the mechanism-based CYP3A inhibitor troleandomycin. Whereas some inhibition of DZAL formation was observed in the presence of 200 mu M diethyldithiocarbamate, 5-50 mu M furafylline, 2-20 mu M sulphaphenazole, 50-500 mu M S-mephenytoin and 1-10 mu M quinidine had little effect.5. Using human B-lymphoblastoid cell microsomes containing cDNA-expressed CYP isoforms, ZAL was metabolized to DZAL by CYP3A4, but not to any great extent by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.6. In contrast with ZAL, the NADPH-dependent N-deethylation of M2 to M1 proceeded at only a very low rate with both human liver microsomes and cDNA-expressed CYP3A4.7. In summary, by correlation analysis, chemical inhibition studies and the use of cDNA-expressed CYPs, ZAL N-deethylation to DZAL in human liver appears to be catalysed by CYP3A isoforms.

  DOI：

  10.1080/004982598239452
• 作为产物：
  描述：

  扎莱普隆 在 aldehyde oxidase 、 1-hydrazinophthalazine 作用下， 以 aq. buffer 为溶剂， 生成 乙酰胺,N-[3-(3-氰基-4,5-二氢-5-羰基吡唑并[1,5-a]嘧啶-7-基)苯基]-N-乙基-
  参考文献：
  名称：

  评估肼屈嗪作为反应表型的醛氧化酶抑制剂的细胞色素P450选择性。

  摘要：

  据报道，肼屈嗪是一种基于选择性机理的醛氧化酶（AO）灭活剂，它在制药行业中广泛用于反应表型分析，以评估AO代谢的组分并鉴定AO底物。然而，在这项研究中，发现肼苯哒嗪在化学表型测定条件下以化学敲除大多数AO活性（≥50μM）的浓度抑制人悬液肝细胞中的CYP1A2、2B6、2D6和3A。此外，肼屈嗪是CYP1A2的时间依赖性抑制剂。基于这些发现，在体外研究中使用肼屈嗪作为AO抑制剂时需要采取预防措施，因为由AO代谢的级分可能被高估，并且在识别AO底物​​时出现假阳性的可能性增加。

  DOI：

  10.1016/j.xphs.2018.11.007

文献信息

• IMMUNODETECTION AND QUANTIFICATION OF PYRAZOLOPYRIMIDINE SEDATIVES
  申请人：Randox Laboratories Ltd.

  公开号：EP2454260B1

  公开（公告）日：2016-11-16
• Evaluation of Cytochrome P450 Selectivity for Hydralazine as an Aldehyde Oxidase Inhibitor for Reaction Phenotyping
  作者：Xin Yang、Nathaniel Johnson、Li Di

  DOI：10.1016/j.xphs.2018.11.007

  日期：2019.4

  Hydralazine has been reported as a selective mechanism-based inactivator of aldehyde oxidase (AO) and it is widely used in the pharmaceutical industry for reaction phenotyping to estimate fraction metabolized by AO and to identify AO substrates. In this study, however, hydralazine was found to inhibit CYP1A2, 2B6, 2D6, and 3A in human suspension hepatocytes under reaction phenotyping assay conditions, at

  据报道，肼屈嗪是一种基于选择性机理的醛氧化酶（AO）灭活剂，它在制药行业中广泛用于反应表型分析，以评估AO代谢的组分并鉴定AO底物。然而，在这项研究中，发现肼苯哒嗪在化学表型测定条件下以化学敲除大多数AO活性（≥50μM）的浓度抑制人悬液肝细胞中的CYP1A2、2B6、2D6和3A。此外，肼屈嗪是CYP1A2的时间依赖性抑制剂。基于这些发现，在体外研究中使用肼屈嗪作为AO抑制剂时需要采取预防措施，因为由AO代谢的级分可能被高估，并且在识别AO底物​​时出现假阳性的可能性增加。
• Metabolism of Zaleplon by human hepatic microsomal cytochrome P450 isoforms
  作者：A. B. RENWICK、H. MISTRY、S. E. BALL、D. G. WALTERS、J. KAO、B. G. LAKE

  DOI：10.1080/004982598239452

  日期：1998.1

  1. The metabolism of Zaleplon (CL-284,846; ZAL) has been studied in human liver microsomal preparations and in cDNA-expressed human cytochrome P450 (CYP) isoforms.2. Human liver microsomes catalysed the NADPH-dependent N-deethylation of ZAL to DZAL (CL-284,859), but not to two other known in vivo metabolites, namely M1 (CL-345,644) and M2 (CL-345,905). Sigmoidal kinetic plots were observed for ZAL deethylation indicating positive cooperativity.3. The metabolism of ZAL to DZAL was determined in a characterized bank of 24 human liver microsomal preparations. Good correlations (r(2) = 0.734-0.937) were observed with caffeine 8-hydroxylase, diazepam 3-hydroxylase, dextromethorphan N-demethylase and testosterone 2 beta-, 6 beta- and 15 beta-hydroxylase activities, which are all catalysed by CYP3A isoforms. In contrast, poor correlations (r(2) = 0.152-0.428) were observed for enzymatic markers for CYP1A2, CYP2A6, CYP2C9/10, CYP2D6, CYP2E1 and CYP4A9/11.4. The metabolism of ZAL to DZAL in human liver microsomes was inhibited to 6-15 % of control by 5-50 mu M of the mechanism-based CYP3A inhibitor troleandomycin. Whereas some inhibition of DZAL formation was observed in the presence of 200 mu M diethyldithiocarbamate, 5-50 mu M furafylline, 2-20 mu M sulphaphenazole, 50-500 mu M S-mephenytoin and 1-10 mu M quinidine had little effect.5. Using human B-lymphoblastoid cell microsomes containing cDNA-expressed CYP isoforms, ZAL was metabolized to DZAL by CYP3A4, but not to any great extent by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.6. In contrast with ZAL, the NADPH-dependent N-deethylation of M2 to M1 proceeded at only a very low rate with both human liver microsomes and cDNA-expressed CYP3A4.7. In summary, by correlation analysis, chemical inhibition studies and the use of cDNA-expressed CYPs, ZAL N-deethylation to DZAL in human liver appears to be catalysed by CYP3A isoforms.