1-羟基咪达唑仑 | 59468-90-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 中文名称: 1-羟基咪达唑仑
• 英文名称: 1-hydroxymidazolam
• 英文别名: 1'-Hydroxymidazolam；1’-hydroxymidazolam；α-hydroxymidazolam；alpha-hydroxymidazolam；1-hydroxy midazolam；hydroxymidazolam；[8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-1-yl]methanol
• CAS: 59468-90-5
• 化学式: C₁₈H₁₃ClFN₃O
• mdl: MFCD00871458
• 分子量: 341.772
• InChiKey: QHSMEGADRFZVNE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.111
• 拓扑面积：
  50.4
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

1'-羟基咪达唑仑是咪达唑仑在人身体内已知的一种代谢物。

1'-Hydroxymidazolam is a known human metabolite of midazolam.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  1-羟基咪达唑仑 在 二氧化锰 作用下， 以 二氯甲烷 为溶剂， 生成 8-chloro-6-(2-fluoro-phenyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-1-carbaldehyde
  参考文献：
  名称：

  Imidazodiazepines and processes therefor

  摘要：

  新型咪唑苯二氮杂环己烯和它们的类似物可用作抗癫痫药、肌肉松弛剂、抗焦虑药和镇静剂。该类的优选化合物属于咪唑并[1,5-a][1,4]二氮杂环己烯系列，可能具有非常广泛的有机取代基。在本发明的范围内尤其优选的一类包括式中的化合物，其中 R.sub.1 为氢和较低的烷基，最好是甲基；R.sub.3 和 R.sub.5 为氢；R.sub.4 为氢、硝基和卤素，最好是氯，在最优选的实施方式中，当位于咪唑苯二氮杂环的融合苯部位的 8-位时，R.sub.6 为苯基或卤素、硝基或较低烷基取代的苯基，最好是卤素，取代的氟在苯基中的 2-位，R.sub.2 为氢和较低的烷基。

  公开号：

  US04280957A1
• 作为产物：
  描述：

  1-乙酰氧基甲基-8-氯-6-(2-氟苯基)-4H-咪唑并[1,5-a][1,4]苯并二氮杂卓 在 sodium methylate 作用下， 以 甲醇 为溶剂， 生成 1-羟基咪达唑仑
  参考文献：
  名称：

  Imidazodiazepines and processes therefor

  摘要：

  新型咪唑苯二氮杂环己烯和它们的类似物可用作抗癫痫药、肌肉松弛剂、抗焦虑药和镇静剂。该类的优选化合物属于咪唑并[1,5-a][1,4]二氮杂环己烯系列，可能具有非常广泛的有机取代基。在本发明的范围内尤其优选的一类包括式中的化合物，其中 R.sub.1 为氢和较低的烷基，最好是甲基；R.sub.3 和 R.sub.5 为氢；R.sub.4 为氢、硝基和卤素，最好是氯，在最优选的实施方式中，当位于咪唑苯二氮杂环的融合苯部位的 8-位时，R.sub.6 为苯基或卤素、硝基或较低烷基取代的苯基，最好是卤素，取代的氟在苯基中的 2-位，R.sub.2 为氢和较低的烷基。

  公开号：

  US04280957A1

文献信息

• Dynamic Modeling of Cytochrome P450 Inhibition In Vitro: Impact of Inhibitor Depletion on IC₅₀ Shift
  作者：Loren M. Berry、Zhiyang Zhao、Min-Hwa Jasmine Lin

  DOI：10.1124/dmd.113.051508

  日期：2013.7

  The impact of inhibitor depletion on the determination of shifted IC50 (IC50 determined after 30 minutes of preincubation with inhibitor) is examined. In addition, IC50-shift data are analyzed using a mechanistic model that incorporates the processes of inhibitor depletion, as well as reversible and time-dependent inhibition. Anomalies such as a smaller-than-expected shift in IC50 and even increases in IC50 with preincubation were explained by the depletion of inhibitor during the preincubation. The IC50-shift assay remains a viable approach to characterizing a wide range of reversible and time-dependent inhibitors. However, as with more traditional time-dependent inactivation methods, it is recommended that IC50-shift experimental data be interpreted with some knowledge of the magnitude of inhibitor depletion. For the most realistic classification of time-dependent inhibitors using IC50-shift methods, shifted IC50 should be calculated using observed inhibitor concentrations at the end of the incubation rather than nominal inhibitor concentrations. Finally, a mechanistic model that includes key processes, such as competitive inhibition, enzyme inactivation, and inhibitor depletion, can be used to describe accurately the observed IC50 and shifted IC50 curves. For compounds showing an IC50 fold shift >1.5 based on the observed inhibitor concentrations, reanalyzing the IC50-shift data using the mechanistic model appeared to allow for reasonable estimation of K i, KI , and k inact directly from the IC50 shift experiments.

  抑制剂耗竭对偏移IC50（在与抑制剂预孵育30分钟后确定的IC50）的影响进行了研究。此外，利用包含抑制剂耗竭过程以及可逆和时间依赖性抑制的机械模型对IC50偏移数据进行了分析。诸如IC50偏移小于预期甚至在预孵育后IC50增加等异常现象，可以用预孵育期间抑制剂的耗竭来解释。IC50偏移测定仍然是表征广泛的可逆和时间依赖性抑制剂的一种可行方法。然而，与更传统的时间依赖性失活方法一样，建议对IC50偏移实验数据的解读应了解抑制剂耗竭的程度。为了对使用IC50偏移方法的时间依赖性抑制剂进行最真实的分类，偏移的IC50应使用在孵育结束时观察到的抑制剂浓度而非名义抑制剂浓度来计算。最后，包含关键过程（如竞争抑制、酶失活和抑制剂耗竭）的机械模型可以用来准确描述观察到的IC50和偏移IC50曲线。对于在观察到的抑制剂浓度基础上显示IC50折射率大于1.5的化合物，使用机械模型重新分析IC50偏移数据似乎可以合理估算K i、K I和k inact，这些值可以直接从IC50偏移实验中得出。
• Effects of Standardized Medicinal Plant Extracts on Drug Metabolism Mediated by CYP3A4 and CYP2D6 Enzymes
  作者：Clarissa Feltrin、Ingrid Vicente Farias、Louis Pergaud Sandjo、Flávio Henrique Reginatto、Cláudia Maria Oliveira Simões

  DOI：10.1021/acs.chemrestox.0c00182

  日期：2020.9.21

  The use of medicinal plants concomitantly with conventional drugs can result in herb–drug interactions that cause fluctuations in drug bioavailability and consequent therapeutic failure and/or toxic effects. The CYP superfamily of enzymes plays an important role in herb–drug interactions. Among CYP enzymes, CYP3A4 and CYP2D6 are the most relevant since they metabolize about 50% and 30% of the drugs on the market, respectively. Thus, the main goal of this study was to evaluate the occurrence of in vitro interactions between medicinal plant extracts and drug substrates of CYP3A4 and CYP2D6 enzymes. Standardized extracts from nine medicinal plants (Bauhinia forficata, Cecropia glaziovii, Cimicifuga racemosa, Cynara scolymus, Echinacea sp., Ginkgo biloba, Glycine max, Ilex paraguariensis, and Matricaria recutita) were evaluated for their potential interactions mediated by CYP3A4 and CYP2D6 enzymes. Among the extracts tested, C. glaziovii (red embaúba) showed the most relevant inhibitory effects of CYP3A4 and CYP2D6 activity, while I. paraguariensis (yerba mate) inhibited CYP3A4 activity. Both extracts were chemically analyzed by UPLC-MS/MS, and these inhibitory effects could lead to clinically potential and relevant interactions with the drug substrates of these isoenzymes.

  使用药用植物与常规药物同时进行可能导致草药-药物相互作用，从而引起药物生物利用度波动，导致治疗失败和/或毒性效应。CYP超家族酶在草药-药物相互作用中扮演着重要角色。在CYP酶中，CYP3A4和CYP2D6最为相关，因为它们分别代谢市场上约50%和30%的药物。因此，本研究的主要目标是评估药用植物提取物与CYP3A4和CYP2D6酶药物底物之间的体外相互作用。对九种药用植物（Bauhinia forficata、Cecropia glaziovii、Cimicifuga racemosa、Cynara scolymus、Echinacea sp.、Ginkgo biloba、Glycine max、Ilex paraguariensis 和 Matricaria recutita）的标准化提取物进行了评估，以探讨其通过CYP3A4和CYP2D6酶介导的潜在相互作用。在测试的提取物中，C. glaziovii（红巴西木）表现出了对CYP3A4和CYP2D6活性最显著的抑制效果，而I. paraguariensis（马黛茶）则抑制了CYP3A4的活性。这两种提取物均通过UPLC-MS/MS进行了化学分析，这些抑制效应可能导致与这些同种酶药物底质的临床潜在和相关相互作用。
• 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。
• Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A
  作者：Jingjing Wu、Yunfeng Cao、Yanyan Zhang、Yong Liu、James Y. Hong、Liangliang Zhu、Guangbo Ge、Ling Yang

  DOI：10.1124/dmd.113.053884

  日期：2014.1

  range of substrate substitutions and that follow the Michaelis-Menten kinetic properties is highly necessary. In the present study, the oxidative pathways of deoxyschizandrin (DS), the most abundant lignan in Fructus Schisandrae fruit extract, were characterized with liver microsomes from human (HLM) and rat (RLM). Only one monohydroxylated metabolite 7(S)-hydroxylated metabolite (isoschizandrin, ISZ)

  为了准确预测细胞色素 P450 (P450) 3A 酶在代谢过程中所做的修饰，选择最能代表广泛的底物置换范围并遵循 Michaelis-Menten 动力学特性的底物是非常必要的。在本研究中，五味子果实提取物中最丰富的木脂素脱氧五味子素 (DS) 的氧化途径用人 (HLM) 和大鼠 (RLM) 的肝微粒体进行表征。使用液相色谱-质谱法和核磁共振技术仅鉴定了一种单羟基化代谢物 7(S)-羟基化代谢物（异五味子素，ISZ）。发现 CYP3A4 和 CYP3A5 是参与 DS 单羟基化的主要同种型。还，动力学研究表明，DS 羟基化在 HLM 和 RLM 中均遵循 Michaelis-Menten 动力学。然而，当 DS 存在时，ISZ 的后续代谢几乎不存在。更重要的是，研究了 DS 与三种充分表征的 CYP3A 探针底物睾酮 (TST)、咪达唑仑 (MDZ) 和硝苯地平 (NIF) 之间的相互作用。TST
• Expression and Characterization of Cynomolgus Monkey Cytochrome CYP3A4 in a Novel Human Embryonic Kidney Cell–Based Mammalian System
  作者：Sindhuja Selvakumar、Priyadeep Bhutani、Kaushik Ghosh、Prasad Krishnamurthy、Sanjith Kallipatti、Sabariya Selvam、Manjunath Ramarao、Sandhya Mandlekar、Michael W. Sinz、A. David Rodrigues、Murali Subramanian

  DOI：10.1124/dmd.113.055491

  日期：2014.3

  Cynomolgus monkeys are a commonly used species in preclinical drug discovery, and have high genetic similarity to humans, especially for the drug-metabolizing cytochrome P450s. However, species differences are frequently observed in the metabolism of drugs between cynomolgus monkeys and humans, and delineating these differences requires expressed CYPs. Toward this end, cynomolgus monkey CYP3A4 (c3A4) was cloned and expressed in a novel human embryonic kidney 293-6E cell suspension system. Following the preparation of microsomes, the kinetic profiles of five known human CYP3A4 (h3A4) substrates (midazolam, testosterone, terfenadine, nifedipine, and triazolam) were determined. All five substrates were found to be good substrates of c3A4, although some differences were observed in the K m values. Overall, the data suggest a strong substrate similarity between c3A4 and h3A4. Additionally, c3A4 exhibited no activity against non-h3A4 probe substrates, except for a known human CYP2D6 substrate (bufuralol), which suggests potential metabolism of human cytochrome CYP2D6-substrates by c3A4. Ketoconazole and troleandomycin showed similar inhibitory potencies toward c3A4 and h3A4, whereas non-h3A4 inhibitors did not inhibit c3A4 activity. The availability of a c3A4 preparation, in conjunction with commercially available monkey liver microsomes, will support further characterization of the cynomolgus monkey as a model to assess CYP3A-dependent clearance and drug-drug interactions.

  猴是临床前药物发现中常用的物种，其基因与人类高度相似，尤其是药物代谢细胞色素 P450s。然而，在猴与人之间的药物代谢过程中经常会观察到物种差异，要确定这些差异需要表达的 CYPs。为此，研究人员克隆了猴 CYP3A4（c3A4），并在新型人胚肾 293-6E 细胞悬浮系统中进行了表达。制备微粒体后，测定了五种已知人类 CYP3A4（h3A4）底物（咪达唑仑、睾酮、特非那定、硝苯地平和三唑仑）的动力学特征。尽管 K m 值存在一些差异，但所有五种底物都是 c3A4 的良好底物。总体而言，数据表明 c3A4 和 h3A4 底物具有很强的相似性。此外，除了已知的人类 CYP2D6 底物（糠醛醇）外，c3A4 对非 h3A4 探针底物没有表现出活性，这表明 c3A4 对人类细胞色素 CYP2D6 底物有潜在的代谢作用。酮康唑和曲安奈德霉素对 c3A4 和 h3A4 的抑制效力相似，而非 h3A4 抑制剂对 c3A4 活性没有抑制作用。c3A4制剂和市售猴肝微粒体的出现将有助于进一步确定猴作为模型的特性，以评估CYP3A依赖性清除和药物相互作用。