5-chloro-2-(furan-2-yl)-8-methyl-pyrazolo-[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine | 1410220-36-8

• 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: 5-chloro-2-(furan-2-yl)-8-methyl-pyrazolo-[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine
• 英文别名: 5-chloropyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine；7-Chloro-4-(furan-2-yl)-11-methyl-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(12),2,4,7,9-pentaene；7-chloro-4-(furan-2-yl)-11-methyl-3,5,6,8,10,11-hexazatricyclo[7.3.0.02,6]dodeca-1(12),2,4,7,9-pentaene
• CAS: 1410220-36-8
• 化学式: C₁₁H₇ClN₆O
• 分子量: 274.669
• InChiKey: CJWRBDJNYXSMRT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  74
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-chloro-2-(furan-2-yl)-8-methyl-pyrazolo-[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 在 盐酸 、 三乙胺 作用下， 以 乙醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 51.0h， 生成 5-(3-(3-((2-(furan-2-yl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino)propyl)thioureido)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid
  参考文献：
  名称：

  吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶开发靶向腺苷受体的功能化配体：以荧光配体为例。

  摘要：

  开发了一系列带有反应性接头的腺苷受体拮抗剂。这些衍生物的功能化可用于轻松获得多靶点配体、受体探针、药物递送系统以及诊断或治疗诊断系统。选择吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶支架作为腺苷受体的药效基团。它在 5 位被不同长度的反应性接头取代。然后，这些化合物通过荧光部分的功能化来合成腺苷受体的探针。评估了这两个系列的化合物与四种腺苷受体亚型的结合。观察到对 hA1、hA2A 和 hA3 腺苷受体的不同亲和力和选择性特征。特别是，荧光化合物充当双 hA2A/hA3 配体。计算研究表明已开发的化合物在三种受体上具有不同的结合模式。分子对接和监督分子动力学 (SuMD) 模拟均证实，单个受体的首选结合模式是由 5 位上的取代驱动的。获得的结果合理化了化合物在腺苷受体上的结合特征，并为开发针对这些膜受体的更有效的可缀合和缀合配体铺平了道路。

  DOI：

  10.1039/c9md00014c
• 作为产物：
  描述：

  4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-methyl-1H-pyrazol-3-amine 在 吡啶 、 五氯化磷 、 三氯氧磷 作用下， 以 1,4-二氧六环 为溶剂， 反应 25.5h， 生成 5-chloro-2-(furan-2-yl)-8-methyl-pyrazolo-[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine
  参考文献：
  名称：

  Exploring the Directionality of 5-Substitutions in a New Series of 5-Alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine as a Strategy To Design Novel Human A₃ Adenosine Receptor Antagonists.

  摘要：

  The structure-activity relationship (SAR) of new 5-alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as antagonists of the A(3) adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A(3) AR. All the synthesized compounds showed affinity for the hA(3) AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (S) alpha-phenylethylamino moiety at the 5 position (26, K-i hA(3) = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N-5 position toward the extracellular environment.

  DOI：

  10.1021/jm300899q

文献信息

• Potent and selective A₃ adenosine receptor antagonists bearing aminoesters as heterobifunctional moieties
  作者：Stephanie Federico、Enrico Margiotta、Stefano Moro、Sonja Kachler、Karl-Norbert Klotz、Giampiero Spalluto

  DOI：10.1039/d0md00380h

  日期：——

  reported compounds are potent hA3 adenosine receptor antagonists and some of them exhibited high selectivity against the other adenosine receptors. The main structural terms of ligand recognition and selectivity were disclosed by molecular modelling studies. Molecular docking results led to the characterization of an alternative binding mode for antagonists at the orthosteric binding site of the hA3 adenosine

  A 3腺苷受体被发现在不同的病理状态中起作用，例如青光眼、肾纤维化、神经性疼痛和癌症。因此，重要的是利用任何有助于研究这些条件的分子工具。在本研究中，我们继续寻找有效的 A 3腺苷受体配体，这些配体可以连续与其他分子偶联，目的是获得更有效的（例如变构配体偶联）或可检测的配体（例如荧光分子或生物素偶联）。具体而言，在吡唑并[4,3 - e ]-1,2,4-三唑并[1,5- c ]的5位引入了不同的氨基酯部分。]嘧啶核。酯官能化代表后续缀合的候选。所有报道的化合物都是有效的 hA 3腺苷受体拮抗剂，其中一些对其他腺苷受体表现出高选择性。分子模型研究揭示了配体识别和选择性的主要结构术语。分子对接结果导致在 hA 3腺苷受体的正构结合位点处对拮抗剂的替代结合模式进行表征，通过经典分子动力学模拟进行评估和评估。
• Revisiting a Receptor-Based Pharmacophore Hypothesis for Human A_2A Adenosine Receptor Antagonists
  作者：Magdalena Bacilieri、Antonella Ciancetta、Silvia Paoletta、Stephanie Federico、Sandro Cosconati、Barbara Cacciari、Sabrina Taliani、Federico Da Settimo、Ettore Novellino、Karl Norbert Klotz、Giampiero Spalluto、Stefano Moro

  DOI：10.1021/ci300615u

  日期：2013.7.22

  The application of both structure- and ligand-based design approaches represents to date one of the most useful strategies in the discovery of new drug candidates. In the present paper, we investigated how the application of docking-driven conformational analysis can improve the predictive ability of 3D-QSAR statistical models. With the use of the crystallographic structure in complex with the high affinity antagonist ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo [2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol), we revisited a general pharmacophore hypothesis for the human A(2A) adenosine receptor of a set of 751 known antagonists, by applying an integrated ligand- and structure-based approach. Our novel pharmacophore hypothesis has been validated by using an external test set of 29 newly synthesized human adenosine receptor antagonists.
• Exploring the Directionality of 5-Substitutions in a New Series of 5-Alkylaminopyrazolo[4,3-<i>e</i>]1,2,4-triazolo[1,5-<i>c</i>]pyrimidine as a Strategy To Design Novel Human A₃ Adenosine Receptor Antagonists.
  作者：Stephanie Federico、Antonella Ciancetta、Davide Sabbadin、Silvia Paoletta、Giorgia Pastorin、Barbara Cacciari、Karl Norbert Klotz、Stefano Moro、Giampiero Spalluto

  DOI：10.1021/jm300899q

  日期：2012.11.26

  The structure-activity relationship (SAR) of new 5-alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as antagonists of the A(3) adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A(3) AR. All the synthesized compounds showed affinity for the hA(3) AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (S) alpha-phenylethylamino moiety at the 5 position (26, K-i hA(3) = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N-5 position toward the extracellular environment.
• Pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]pyrimidines to develop functionalized ligands to target adenosine receptors: fluorescent ligands as an example
  作者：Stephanie Federico、Enrico Margiotta、Silvia Paoletta、Sonja Kachler、Karl-Norbert Klotz、Kenneth A. Jacobson、Giorgia Pastorin、Stefano Moro、Giampiero Spalluto

  DOI：10.1039/c9md00014c

  日期：——

  A series of adenosine receptor antagonists bearing a reactive linker was developed. Functionalization of these derivatives is useful to easily obtain multi-target ligands, receptor probes, drug delivery systems, and diagnostic or theranostic systems. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold was chosen as a pharmacophore for the adenosine receptors. It was substituted at the 5 position

  开发了一系列带有反应性接头的腺苷受体拮抗剂。这些衍生物的功能化可用于轻松获得多靶点配体、受体探针、药物递送系统以及诊断或治疗诊断系统。选择吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶支架作为腺苷受体的药效基团。它在 5 位被不同长度的反应性接头取代。然后，这些化合物通过荧光部分的功能化来合成腺苷受体的探针。评估了这两个系列的化合物与四种腺苷受体亚型的结合。观察到对 hA1、hA2A 和 hA3 腺苷受体的不同亲和力和选择性特征。特别是，荧光化合物充当双 hA2A/hA3 配体。计算研究表明已开发的化合物在三种受体上具有不同的结合模式。分子对接和监督分子动力学 (SuMD) 模拟均证实，单个受体的首选结合模式是由 5 位上的取代驱动的。获得的结果合理化了化合物在腺苷受体上的结合特征，并为开发针对这些膜受体的更有效的可缀合和缀合配体铺平了道路。