4-(3-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)propyl)phenol | 188112-92-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并嘧啶类
• 英文名称: 4-(3-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)propyl)phenol
• 英文别名: SCH442416；Desmethyl SCH 442416；4-[3-[7-amino-4-(furan-2-yl)-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,11-pentaen-10-yl]propyl]phenol
• CAS: 188112-92-7
• 化学式: C₁₉H₁₇N₇O₂
• 分子量: 375.39
• InChiKey: AXDUXMMFIPBLRQ-UHFFFAOYSA-N

物化性质

• 熔点：
  189-191 °C
• 密度：
  1.58±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-(3-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)propyl)phenol 在 水 、 caesium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 16.0h， 生成 2-(4-(3-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)propyl)phenoxy)acetic acid
  参考文献：
  名称：

  Molecular probes for the A2A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold

  摘要：

  Pyrazolo[4,3-e][1,2,4] triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A(2A) adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for F-18 incorporation), and fluorophore reporter groups (e. g., BODIPY conjugate 14, K-i 15 nM). The potent and A(2A)AR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A(2A)AR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A(2A)AR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A(2A)AR. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2010.11.082
• 作为产物：
  描述：

  2-呋喃甲酰肼 在 palladium on activated charcoal N-甲基吡咯烷酮 、 盐酸 、 氢气 、 对甲苯磺酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 25.0~260.0 ℃ 、344.73 kPa 条件下， 反应 8.5h， 生成 4-(3-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)propyl)phenol
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of a Second Generation of Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as Potent and Selective A_2A Adenosine Receptor Antagonists

  摘要：

  New A(2A) adenosine receptor antagonists in the series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]-pyrimidines, bearing oxygenated substituents on the phenylalkyl chains on the 7-position, have been synthesized. The compounds were tested in binding and functional assays to evaluate affinity, potency, and selectivity for rat A(2A) compared to rat A(1) and human A(3) receptor subtypes. The most interesting compounds (5d,e,h) were tested also in binding to human A(1) and A(2A) adenosine receptors. They showed very good affinity (K-i = 0.94 nM for compound 5h) and interesting selectivity with respect to both rA(1) and hA(3) (compound 5h: rA(1)/rA(2A) = 787, hA(3)/rA(2A) > 10000) These important findings make this new series of compounds the first really selective for A(2A) adenosine receptors. Thermodynamic parameters were evaluated; all the tested compounds displayed an enthalpy-driven binding as expected for antagonists. Moreover, compound 5h showed a negative entropy value. The highly negative enthalpic and entropic contributions could mean that 5h fits very well in the binding site where, probably, an electrostatic interaction is present associated to a scarce solvent reorganization around the receptor binding site. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.

  DOI：

  10.1021/jm9708689

文献信息

• Bitopic fluorescent antagonists of the A_2A adenosine receptor based on pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine functionalized congeners
  作者：Romain Duroux、Antonella Ciancetta、Philip Mannes、Jinha Yu、Shireesha Boyapati、Elizabeth Gizewski、Said Yous、Francisco Ciruela、John A. Auchampach、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1039/c7md00247e

  日期：——

  Functionalized antagonist probes of the A_2A adenosine receptor.

  A_2A腺苷受体的功能化拮抗探针。
• Synthesis and evaluation of 1,2,4-triazolo[1,5-c]pyrimidine derivatives as A2A receptor-selective antagonists
  作者：Bidhan A. Shinkre、T. Santhosh Kumar、Zhan-Guo Gao、Francesca Deflorian、Kenneth A. Jacobson、William C. Trenkle

  DOI：10.1016/j.bmcl.2010.08.021

  日期：2010.10

  Movement disorders such as Parkinson’s disease and Huntington’s disease are serious life-limiting and debilitating movement disorders. Their onset typically occurs from mid-life to late in life, and effective diagnostic techniques for detecting and following the disease course are lacking. Our goal is to develop receptor imaging agents for positron emission tomography (PET) that selectively target

  帕金森病和亨廷顿病等运动障碍是严重的限制生命和使人衰弱的运动障碍。它们的发病通常发生在中年至晚年，并且缺乏用于检测和跟踪病程的有效诊断技术。我们的目标是开发用于正电子发射断层扫描 (PET) 的受体显像剂，它选择性地靶向在纹状体中高度表达的最相关的腺苷受体 (AR) 亚型，即 A 2A AR。为了进一步实现这一目标，我们已经合成并在药理学上表征了一系列高亲和力 A 2A AR 配体，基于已知的拮抗剂 SCH 442416 (R = -Me)，其末端具有结构可变性 (R = -Et, -一世-Pr、-allyl 等）。适合用作PET示踪剂的O-氟乙基类似物的K i值为12.4 nM，并且与A 1和A 3 AR相比对A 2A AR具有高度选择性。
• PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy
  作者：Susann Schröder、Thu Hang Lai、Magali Toussaint、Mathias Kranz、Alexandra Chovsepian、Qi Shang、Sladjana Dukić-Stefanović、Winnie Deuther-Conrad、Rodrigo Teodoro、Barbara Wenzel、Rareş-Petru Moldovan、Francisco Pan-Montojo、Peter Brust

  DOI：10.3390/molecules25071633

  日期：——

  aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A2AR upregulation in PD. For that purpose, we selected the known A2AR-specific radiotracer [18F]FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [18F]FESCH in the mouse striatum

  腺苷 A2A 受体 (A2AR) 被认为是非多巴胺能治疗帕金森病 (PD) 的特别合适的靶点。在 PD 早期阶段的人类纹状体以及患有 PD 和运动障碍的患者中发现 A2AR 可用性增加。这项小动物正电子发射断层扫描/磁共振 (PET/MR) 成像研究的目的是研究鱼藤酮治疗的小鼠是否反映了 PD 纹状体 A2AR 上调的方面。为此，我们选择了已知的 A2AR 特异性放射性示踪剂 [18F]FESCH，并开发了一种简化的两步一锅法放射性合成。PET 图像显示小鼠纹状体中 [18F]FESCH 的高摄取。同时，[18F]FESCH 的代谢研究揭示了脑渗透性放射性代谢物的存在。在鱼藤酮处理的小鼠中，发现 [18F]FESCH 的纹状体 A2AR 结合略高。尽管如此，所提出的 PD 动物模型中 A2AR 水平增加之间的相关性仍有待进一步研究。
• Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability
  作者：Thu Hang Lai、Magali Toussaint、Rodrigo Teodoro、Sladjana Dukić-Stefanović、Daniel Gündel、Friedrich-Alexander Ludwig、Barbara Wenzel、Susann Schröder、Bernhard Sattler、Rareş-Petru Moldovan、Björn H. Falkenburger、Osama Sabri、Winnie Deuther-Conrad、Peter Brust

  DOI：10.1007/s00259-020-05164-4

  日期：2021.8

  The adenosine A_2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A_2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A_2A receptor radiotracer and report herein the preclinical evaluation of [¹⁸F]FLUDA, a deuterated isotopologue of [¹⁸F]FESCH.

  [¹⁸F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats.

  [¹⁸F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A_2A receptor–specific accumulation of [¹⁸F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [¹⁸F]FLUDA compared to that of [¹⁸F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [¹⁸F]FLUDA towards striatal A_2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [¹⁸F]FLUDA.

  The new radiotracer [¹⁸F]FLUDA is suitable to detect the availability of the A_2A receptor in the brain with high target specificity. It is regarded ready for human application.

  摘要 目的：腺苷A2A受体已成为多种疾病的治疗靶点，因此非侵入性成像A2A受体的表达或占位有潜力为诊断和药物开发做出贡献。我们旨在开发一种代谢稳定的A2A受体放射性示踪剂，并在此处报告[18F]FLUDA的临床前评估，它是[18F]FESCH的氘同位素。 方法：[18F]FLUDA通过两步一锅法合成，并通过体外放射自显影研究以及小鼠和仔猪的代谢和动态PET / MRI研究在基线和阻断条件下进行体内评估。在大鼠中进行了单剂量毒性研究。 结果：[18F]FLUDA的放射化学收率为19％，摩尔活性为72-180 GBq /μmol。自显影证明了小鼠和猪脑中[18F]FLUDA在纹状体中的A2A受体特异性积累。小鼠体内评估显示[18F]FLUDA的稳定性优于[18F]FESCH，导致无脑可渗透放射性代谢物。此外，仔猪检测到的放射性代谢物预计具有较低的大脑穿透倾向。PET / MRI研究证实[18F]FLUDA对纹状体A2A受体具有高度特异性结合，小鼠的最大特异性结合比为8.3。毒性研究显示[18F]FLUDA在30 μg / kg（约为人类PET研究中应用的剂量的4000倍）时没有不良影响。 结论：新的放射性示踪剂[18F]FLUDA适用于检测大脑中A2A受体的可用性，具有高度的靶点特异性。它被认为已准备好应用于人体。
• Automated radiosynthesis of the adenosine A _2A receptor‐targeting radiotracer [ ¹⁸ F]FLUDA
  作者：Thu Hang Lai、Barbara Wenzel、Rareş‐Petru Moldovan、Peter Brust、Klaus Kopka、Rodrigo Teodoro

  DOI：10.1002/jlcr.3970

  日期：2022.5.30

  [18 F]FLUDA is a selective radiotracer for in vivo imaging of the adenosine A2A receptor (A2A R) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [18 F]FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [18 F]FLUDA using a GE TRACERlab FX2 N radiosynthesizer

  [18 F]FLUDA 是一种选择性放射性示踪剂，用于通过正电子发射断层扫描 (PET) 对腺苷 A2A 受体 (A2A R) 进行体内成像。通过小鼠和仔猪的神经影像学获得的有希望的临床前结果表明 [18 F] FLUDA 可用于人类 PET 研究。因此，我们在此报告了使用 GE TRACERlab FX2 N 放射合成仪对 [18 F]FLUDA 进行远程控制的自动放射合成。该放射性示踪剂采用一锅二步放射性氟化法获得，放射化学收率9±1%，放射化学纯度≥99%，合成结束时摩尔活度在69-333 GBq/μmol范围内。在大约的总合成时间内。95 分钟（n = 16）。总而言之，我们成功地建立了一种可靠且可重复的 [18 F] FLUDA 自动化生产程序。