去乙基阿莫地喹 | 79352-78-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 去乙基阿莫地喹
• 中文别名: 氮位N-去乙基二盐酸阿莫地喹
• 英文名称: N-desethylamodiaquine
• 英文别名: 7-chloro-4-<α-(ethylamino)-4-hydroxy-m-toluidino>quinoline；N‐desethylamodiaquine；monodesethyl amodiaquine；monodesethyl-amodiaquine；monodesethylamodiaquine；Desethylamodiaquine；4-[(7-chloroquinolin-4-yl)amino]-2-(ethylaminomethyl)phenol
• CAS: 79352-78-6
• 化学式: C₁₈H₁₈ClN₃O
• 分子量: 327.813
• InChiKey: VRXFDHAGFYWGHT-UHFFFAOYSA-N

物化性质

• 熔点：
  168-174°C
• 沸点：
  477.8±45.0 °C(Predicted)
• 密度：
  1.304±0.06 g/cm3(Predicted)
• 溶解度：
  甲醇（微溶）、水（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  57.2
• 氢给体数：
  3
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20°C，密闭保存，干燥环境中存放

制备方法与用途

生物活性方面，N-Desethyl amodiaquine 是 Amodiaquine 的主要生物活性代谢产物。这种抗寄生虫剂对菌株 V1/S 和 3D7 的 IC50 值分别为 97 nM 和 25 nM。

反应信息

• 作为反应物：
  描述：

  去乙基阿莫地喹 、 N,N-二乙基氯甲酰胺 在 三乙胺 作用下， 以 氯仿 为溶剂， 以80%的产率得到7-chloro-4-<α--4-hydroxy-m-toluidino>quinoline
  参考文献：
  名称：

  合成一些新的氨二喹类似物作为潜在的抗疟和抗孝化合物。

  摘要：

  设计并合成了十个氨二喹类似物，它们是氨二喹和二乙基氨基甲嗪的杂交分子。六种类似物均在其侧链上具有基本的叔氨基功能，它们在小鼠中对伯氏疟原虫具有活性，并在体外抑制成虫的活动性和Breinlia booliati的微丝虫。它们对纳塔氏乳杆菌中的Litomosoides carinii没有活性。最具活性的抗疟疾化合物7-氯-4- [α-[[N-（4-甲基-1-哌嗪基）羰基]氨基] -4-羟基-间甲苯基]喹啉的活性是氨二喹的两倍。O-甲基化和N-乙基化通常会降低抗疟活性。在其侧链上缺乏基本叔氨基功能的类似物在抗疟和抗孝活性上也都缺乏。

  DOI：

  10.1021/jm00144a020
• 作为产物：
  描述：

  阿莫地喹 在 amodiaquine N‐deethylase 作用下， 反应 0.25h， 生成 去乙基阿莫地喹
  参考文献：
  名称：

  乙酰紫草素是一种新型的非选择性细胞色素P450抑制剂。

  摘要：

  乙酰紫草素是一种具有抗癌和抗炎活性的生物活性化合物，它是从紫草紫薇的根中分离出来的。最近发现乙酰紫草素对CYP2J2活性的抑制作用。基于此结果，本研究扩展到使用底物混合物温育测定法评估乙酰基紫草素对人肝微粒体（HLM）中9种不同的细胞色素P450（P450）同工型的抑制作用。乙酰紫草素对所有测试的P450表现出强烈的抑制作用，IC50值为1.4-4.0μm。乙酰紫草素与HLM和NADPH的预孵育不会改变抑制效果，表明乙酰紫草素不是基于机理的抑制剂。SKF-525A是一种广泛使用的非特异性P450抑制剂，对CYP1A2、2A6、2E1和2J2没有抑制活性，而对CYP2B6，CYP2C19和2D6表现出抑制作用，IC50值分别为2.5、3.6和0.5μm。我们的发现表明，乙酰紫草素可能是一种新型的通用P450抑制剂，可以代替SKF-525A。

  DOI：

  10.1002/bdd.2101

文献信息

• Nanoporous Gold Catalyst for the Oxidative N‐Dealkylation of Drug Molecules: A Method for Synthesis of N‐Dealkylated Metabolites
  作者：Ali Alipour Najmi、Elchin Jafariyeh‐Yazdi、Mojgan Hadian、Jos Hermans、Rainer Bischoff、Jun Yue、Alexander Dömling、Arne Wittstock、Hjalmar P. Permentier

  DOI：10.1002/cmdc.202200040

  日期：2022.6.3

  Facilitating drug discovery: We describe a novel method for the selective catalytic N-dealkylation of drug molecules on a nanoporous gold (NPG) catalyst producing valuable N-dealkylated metabolites and intermediates. Various examples examined in this study showed that aerobic catalytic N-dealkylation of drug molecules on NPG has a broad scope, supporting N-deethylation, N-deisopropylation and N-demethylation

  促进药物发现：我们描述了一种在纳米多孔金 (NPG) 催化剂上选择性催化 N-脱烷基化药物分子的新方法，可产生有价值的 N-脱烷基代谢物和中间体。本研究中检查的各种示例表明，药物分子在 NPG 上的有氧催化 N-脱烷基化具有广泛的范围，支持 N-去乙基化、N-去异丙基化和 N-去甲基化，将 3° 胺转化为 2° 胺或 2° 胺至 1° 胺。
• Drug metabolism by CYP2C8.3 is determined by substrate dependent interactions with cytochrome P450 reductase and cytochrome b5
  作者：Rüdiger Kaspera、Suresh B. Naraharisetti、Eric A. Evangelista、Kristin D. Marciante、Bruce M. Psaty、Rheem A. Totah

  DOI：10.1016/j.bcp.2011.06.027

  日期：2011.9

  Genetic polymorphisms in CYP2C8 can influence the metabolism of important therapeutic agents and cause interindividual variation in drug response and toxicity. The significance of the variant CYP2C8*3 has been controversial with reports of higher in vivo but lower in vitro activity compared to CYP2C8*1. In this study, the contribution of the redox partners cytochrome P450 reductase (CPR) and cytochrome b5 to the substrate dependent activity of CYP2C8.3 (R139K, K399R) was investigated in human liver microsomes (HLMs) and Escherichia call expressed recombinant CYP2C8 proteins using amodiaquine, paclitaxel, rosiglitazone and cerivastatin as probe substrates. For recombinant CYP2C8.3, clearance values were two- to five-fold higher compared to CYP2C8.1. CYP2C8.3's higher k(cat) seems to be dominated by a higher, but substrate specific affinity, towards cytochrome b5 and CPR (K(D) and K(m,red)) which resulted in increased reaction coupling. A stronger binding affinity of ligands to CYP2C8.3, based on a two site binding model, in conjunction with a five fold increase in amplitude of heme spin change during binding of ligands and redox partners could potentially contribute to a higher k(cat), in HLMs, carriers of the CYP2C8*1/*3 genotype were as active as CYP2C8*1/*1 towards the CYP2C8 specific reaction amodiaquine N-deethylation. Large excess of cytochrome b5 compared to CYP2C8 in recombinant systems and HLMs inhibited metabolic clearance, diminishing the difference in k(cat) between the two enzymes, and may provide an explanation for the discrepancy to in vivo data. In silico studies illustrate the genetic differences between wild type and variant on the molecular level. (C) 2011 Elsevier Inc. All rights reserved.
• Identification of human cytochrome P 450 s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data
  作者：Xue-Qing Li、Anders Bj�rkman、Tommy B. Andersson、Lars L. Gustafsson、Collen M. Masimirembwa

  DOI：10.1007/s00228-003-0636-9

  日期：2003.9.1

  Objective. Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P-450 (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data.Methods. In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P-450 (rCYP), were used to determine the intrinsic clearance (CLint) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs.Results and discussion. CLint determined in RLM and HLM showed low (r(2)=0.50) but significant (P<0.01) correlation. The CLint values were scaled to predict in vivo hepatic clearance (CLH) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CLH predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (>70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (<30% liver blood flow; chloroquine, dapsone, diethylcarbamazine, pentamidine, primaquine, pyrantel, pyrimethamine, tinidazole) and intermediate clearance drugs (artemisinin, artesunate, quinine). With the exception of artemisinin, which is a high clearance drug in vivo, all other compounds were classified using in vitro data in agreement with in vivo observations. We identified hepatic CYP enzymes responsible for metabolism of some compounds (praziquantel-1A2, 2C19, 3A4; primaquine-1A2, 3A4; chloroquine-2C8, 2D6, 3A4; artesunate-2A6; pyrantel-2D6). For the other compounds, we confirmed the role of previously reported CYPs for their metabolism and identified other CYPs involved which had not been reported before.Conclusion. Our results show that it is possible to make in vitro-in vivo predictions of high, intermediate and low CLint drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.
• Engineering Macaca fascicularis cytochrome P450 2C20 to reduce animal testing for new drugs
  作者：Francesco Rua、Sheila J. Sadeghi、Silvia Castrignanò、Giovanna Di Nardo、Gianfranco Gilardi

  DOI：10.1016/j.jinorgbio.2012.05.017

  日期：2012.12

  In order to develop in vitro methods as an alternative to P450 animal testing in the drug discovery process, two main requisites are necessary: 1) gathering of data on animal homologues of the human P450 enzymes, currently very limited, and 2) bypassing the requirement for both the P450 reductase and the expensive cofactor NADPH. In this work, P450 2C20 from Macaca fascicularis, homologue of the human P450 2C8 has been taken as a model system to develop such an alternative in vitro method by two different approaches. In the first approach called "molecular Lego", a soluble self-sufficient chimera was generated by fusing the P450 2C20 domain with the reductase domain of cytochrome P450 BM3 from Bacillus megaterium (P450 2C20/BMR). In the second approach, the need for the redox partner and also NADPH were both obviated by the direct immobilization of the P450 2C20 on glassy carbon and gold electrodes. Both systems were then compared to those obtained from the reconstituted P450 2C20 monooxygenase in presence of the human P450 reductase and NADPH using paclitaxel and amodiaquine, two typical drug substrates of the human P450 2C8. The K-M values calculated for the 2C20 and 2C20/BMR in solution and for 2C20 immobilized on electrodes modified with gold nanoparticles were 1.9 +/- 0.2, 5.9 +/- 2.3, 3.0 +/- 0.5 mu M for paclitaxel and 1.2 +/- 0.2, 1.6 +/- 0.2 and 1.4 +/- 0.2 mu M for amodiaquine, respectively. The data obtained not only show that the engineering of M. fasciculans did not affect its catalytic properties but also are consistent with K-M values measured for the microsomal human P450 2C8 and therefore show the feasibility of developing alternative in vitro animal tests. (C) 2012 Elsevier Inc. All rights reserved.
• Functional characterization of 12 allelic variants of CYP2C8 by assessment of paclitaxel 6α-hydroxylation and amodiaquine N-deethylation
  作者：Chiharu Tsukada、Takahiro Saito、Masamitsu Maekawa、Nariyasu Mano、Akifumi Oda、Noriyasu Hirasawa、Masahiro Hiratsuka

  DOI：10.1016/j.dmpk.2015.07.003

  日期：2015.10

  Cytochrome P450 2C8 (CYP2C8) is one of the enzymes primarily responsible for the metabolism of many drugs, including paclitaxel and amodiaquine. CYP2C8 genetic variants contribute to interindividual variations in the therapeutic efficacy and toxicity of paclitaxel. Although it is difficult to investigate the enzymatic function of most CYP2C8 variants in vivo, this can be investigated in vitro using recombinant CYP2C8 protein variants. The present study used paclitaxel to evaluate 6 alpha-hydroxylase activity and amodiaquine for the N-deethylase activity of wild-type and 11 CYP2C8 variants resulting in amino acid substitutions in vitro. The wild-type and variant CYP2C8 proteins were heterologously expressed in COS-7 cells. Paclitaxel 6 alpha-hydroxylation and amodiaquine N-deethylation activities were determined by measuring the concentrations of 6 alpha-hydroxypaclitaxel and N-desethylamodiaquine, respectively, and the kinetic parameters were calculated. Compared to the wild-type enzyme (CYP2C8.1), CYP2C8.11 and CYP2C8.14 showed little or no activity with either substrate. In addition, the intrinsic clearance values of CYP2C8.8 and CYP2C8.13 for paclitaxel were 68% and 67% that of CYP2C8.1, respectively. In contrast, the CLint values of CYP2C8.2 and CYP2C8.12 were 1.4 and 1.9 times higher than that of CYP2C8.1. These comprehensive findings could inform for further genotype-phenotype studies on interindividual differences in CYP2C8-mediated drug metabolism. Copyright (C) 2015, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.