6-methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine | 1156499-27-2

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: 6-methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine
• 英文别名: 6-methoxy-2-(4-methylimidazol-1-yl)-3-nitropyridine
• CAS: 1156499-27-2
• 化学式: C₁₀H₁₀N₄O₃
• 分子量: 234.214
• InChiKey: SJHMTDBGDSDSAV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  85.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine 在 palladium on activated charcoal 、 氢气 作用下， 以 乙醇 为溶剂， 以79%的产率得到6-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridin-3-amine
  参考文献：
  名称：

  18 F标记的咪唑并吡啶三嗪用于环状核苷酸磷酸二酯酶2A分子成像的研究。

  摘要：

  通过正电子发射断层扫描（PET）在体内可视化和定量环核苷酸磷酸二酯酶2A（PDE2A）的特定放射性配体越来越引起大脑研究的兴趣。在这里，我们描述了我们最新的PDE2A（放射性）配体9-（5-丁氧基-2-氟苯基）-2-（2-（[[18F]）氟乙氧基）-的合成，18F标记以及生物学评估。 7-甲基咪唑并[5,1-c]吡啶并[2,3-e] [1,2,4]三嗪（（[18F]）TA5）。到目前为止，它是我们基于咪唑并吡啶并三嗪的系列化合物中最有效的PDE2A配体（IC50 hPDE2A = 3.0 nM； IC50 hPDE10A> 1000 nM）。从相应的甲苯磺酸酯前体开始，以一步步骤进行放射性标记。大鼠和猪脑片的体外放射自显影显示了放射性配体的均质和非特异性结合。通过反相HPLC（RP-HPLC）和胶束液相色谱（MLC）对从小鼠获得的血浆和脑样品进行的体内稳定性研究，发现了一种主要的放射性代谢产物。因此，我们得出结论，[18F]

  DOI：

  10.3390/molecules23030556
• 作为产物：
  描述：

  4-甲基咪唑 、 2-氯-6-甲氧基-3-硝基吡啶 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 氯仿 为溶剂， 以93%的产率得到6-methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine
  参考文献：
  名称：

  18 F标记的咪唑并吡啶三嗪用于环状核苷酸磷酸二酯酶2A分子成像的研究。

  摘要：

  通过正电子发射断层扫描（PET）在体内可视化和定量环核苷酸磷酸二酯酶2A（PDE2A）的特定放射性配体越来越引起大脑研究的兴趣。在这里，我们描述了我们最新的PDE2A（放射性）配体9-（5-丁氧基-2-氟苯基）-2-（2-（[[18F]）氟乙氧基）-的合成，18F标记以及生物学评估。 7-甲基咪唑并[5,1-c]吡啶并[2,3-e] [1,2,4]三嗪（（[18F]）TA5）。到目前为止，它是我们基于咪唑并吡啶并三嗪的系列化合物中最有效的PDE2A配体（IC50 hPDE2A = 3.0 nM； IC50 hPDE10A> 1000 nM）。从相应的甲苯磺酸酯前体开始，以一步步骤进行放射性标记。大鼠和猪脑片的体外放射自显影显示了放射性配体的均质和非特异性结合。通过反相HPLC（RP-HPLC）和胶束液相色谱（MLC）对从小鼠获得的血浆和脑样品进行的体内稳定性研究，发现了一种主要的放射性代谢产物。因此，我们得出结论，[18F]

  DOI：

  10.3390/molecules23030556

文献信息

• Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography
  作者：Susann Schröder、Barbara Wenzel、Winnie Deuther-Conrad、Rodrigo Teodoro、Ute Egerland、Mathias Kranz、Matthias Scheunemann、Norbert Höfgen、Jörg Steinbach、Peter Brust

  DOI：10.3390/molecules20069591

  日期：——

  Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2–4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives.

  磷酸二酯酶2A（PDE2A）在特定的神经疾病受影响的脑区和某些肿瘤中高度特异性表达。开发一种特定的PDE2A放射配体将使得通过正电子发射断层扫描（PET）对PDE2A蛋白进行分子成像成为可能。在此，我们报告了三种新型氟烷基化三嗪衍生物（TA2–4）的合成及其对人类PDE2A酶活性的影响评估。最有效的PDE2A抑制剂为18F标记的（[18F]TA3和[18F]TA4），并对其作为PET放射配体在小鼠脑中成像PDE2A的潜力进行了研究。对大鼠脑进行的体外自放射影像显示，[18F]TA3和[18F]TA4具有区域特异性分布，这与PDE2A蛋白的表达模式一致。对小鼠中[18F]TA3和[18F]TA4的代谢研究显示，每种放射配体在脑中均显著积累了两种主要放射代谢物，且通过胶束放射色谱法进行了探讨。使用[18F]TA3的鼠类PET/MR研究显示，在非靶向区域小脑中活性不断增加的摄取可能是由能穿透脑部的放射代谢物的积累引起的。因此，[18F]TA3和[18F]TA4特别适合于PDE2A的体外研究。然而，进一步对这些有前景的放射配体进行结构改造可能会导致代谢稳定的衍生物。
• Pyrido[3,2-E]Pyrazines, Process For Preparing The Same, And Their Use As Inhibitors Of Phosphodiesterase 10
  申请人：Malamas Michael S.

  公开号：US20090143361A1

  公开（公告）日：2009-06-04

  The invention relates to pyrido[3,2-e]pyrazines, to processes for preparing them, to pharmaceutical compositions which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10, as active compounds for treating central nervous system disorders, obesity, and metabolic disorders.

  这项发明涉及吡啶并[3,2-e]吡嗪化合物，涉及其制备方法，包括这些化合物的药物组成物以及这些化合物的药用，这些化合物是磷酸二酯酶10的抑制剂，作为治疗中枢神经系统疾病、肥胖和代谢紊乱的活性化合物。
• Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors
  作者：Michael S. Malamas、Yike Ni、James Erdei、Hans Stange、Rudolf Schindler、Hans-Joachim Lankau、Christian Grunwald、Kristi Yi Fan、Kevin Parris、Barbara Langen、Ute Egerland、Thorsten Hage、Karen L. Marquis、Steve Grauer、Julie Brennan、Rachel Navarra、Radka Graf、Boyd L. Harrison、Albert Robichaud、Thomas Kronbach、Menelas N. Pangalos、Norbert Hoefgen、Nicholas J. Brandon

  DOI：10.1021/jm2009138

  日期：2011.11.10

  The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound I and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
• [EN] PYRIDO[3,2-E]PYRAZINES, PROCESS FOR PREPARING THE SAME, AND THEIR USE AS INHIBITORS OF PHOSPHODIESTERASE 10<br/>[FR] PYRIDO[3,2-E]PYRAZINES, LEUR PROCÉDÉ DE PRÉPARATION, ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE PHOSPHODIESTÉRASE 10
  申请人：WYETH CORP

  公开号：WO2009070583A1

  公开（公告）日：2009-06-04

  The invention relates to pyrido[3,2-e]pyrazines, to processes for preparing them, to pharmaceutical compositions which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10, as active compounds for treating central nervous system disorders, obesity, and metabolic disorders.