8-amino-6-(4-hydroxyphenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3(2H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 8-amino-6-(4-hydroxyphenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3(2H)-one
• 英文别名: 8-Amino-6-(4-hydroxyphenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one；8-amino-6-(4-hydroxyphenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one
• 化学式: C₁₇H₁₃N₅O₂
• 分子量: 319.323
• InChiKey: MDIQQNWAXLRRDO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  94.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-amino-6-(4-hydroxyphenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3(2H)-one 在 吡啶 、 氯化亚砜 、 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 18.25h， 生成 8-amino-6-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-2-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3(2H)-one
  参考文献：
  名称：

  新的8-氨基-1,2,4-三唑并[4,3-a]吡嗪-3-一衍生物。评价6-芳基环上的不同部分以获得有效的和选择性的人A2A腺苷受体拮抗剂。

  摘要：

  在这项工作中，对8-氨基-2-苯基-6-芳基-1,2,4-三唑并[4,3-a]吡嗪-3-one系列进行了进一步的结构研究，以实现有力和选择性的人A2A腺苷受体（AR）拮抗剂。不同的醚和酰胺部分连接在6-苯环的对位，因此分别得到化合物1-9和10-18。这些部分大多数包含末端碱性环（吡咯烷，吗啉，哌啶和取代的哌嗪），它们被认为具有良好的理化性质和药物样性质。带有酰胺连接基的化合物11-16对hA2A AR具有高亲和力和选择性（Ki ＝ 3.6-11.8nM）。与相对酰胺化合物相比，具有醚接头的衍生物1-9也优先靶向hA2A AR，但亲和力较低。对接研究

  DOI：

  10.1016/j.bmcl.2020.127126
• 作为产物：
  描述：

  ethyl (phenylhydrazono)chloroacetate 在 ammonium acetate 、 氨 、 三溴化硼 、 potassium carbonate 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 23.25h， 生成 8-amino-6-(4-hydroxyphenyl)-2-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3(2H)-one
  参考文献：
  名称：

  The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A_2A Receptor Subtype

  摘要：

  In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin-3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R-6), was synthesized with the main purpose of targeting the hA(2A) adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA(2A) AR (K-i = 2.910 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA(2A) AR antagonist (12, R = H, R-6 = 4-methoxyphenyl) demonstrated some ability to counteract MPP+-induced neurotoxicity in cultured human neuroblastoma SH-SY5Y cells, a widely used in vitro Parkinsons disease model. Docking studies at hAR structures were performed to rationalize the observed affinity data.

  DOI：

  10.1021/acs.jmedchem.7b00457

文献信息

• ¹⁸F-Labeled PET Tracers Specific for Adenosine A_2A Receptor: Design, Synthesis, and Biological Evaluation
  作者：Tingyu Yang、Wei Zheng、Xuebo Cheng、Hualong Chen、Zeng Jiang、Ziyue Yu、Lu Zhang、Yi Xie、Lianjie Du、Xuan Ge、Jiahuai Zhang、Leilei Yuan、Yajing Liu、Zehui Wu

  DOI：10.1021/acschemneuro.4c00066

  日期：2024.3.20

  were designed and synthesized. In vitro inhibition experiments demonstrated that 3, 12c, and BIBD-399 have high affinity for A2AR. [18F]3 and [18F]BIBD-399 were successfully synthesized. In terms of biological distribution, the brain uptake of [18F]MNI-444 exhibits greater than that of [18F]3 and [18F]BIBD-399. PET imaging shows that [18F]3 is off-target in the brain, while [18F]BIBD-399 and [18F]MNI-444

  通过修饰靶向A 2A R拮抗剂和示踪剂的结构，设计并合成了新化合物3、7a、9、12c和BIBD - 399。体外抑制实验表明3 、 12c和BIBD-399 对A 2A R 具有高亲和力。成功合成了[ 18 F]3和[ 18 F]BIBD-399。就生物分布而言，[ 18 F]MNI-444的脑摄取表现出大于[ 18 F]3和[ 18 F]BIBD-399。 PET 成像显示[ 18 F]3在大脑中脱靶，而 [ 18 F]BIBD-399 和 [ 18 F]MNI-444 可以在 A 2A R 高表达区域特异性成像。不同的是，[ 18 F]BIBD-399在给药后10分钟内即可在目标区域迅速达到平衡，而[ 18 F]MNI-444在给药后2小时内表现出缓慢增加的趋势。 [ 18 F]BIBD-399主要经肝、肾代谢，体内无明显脱氟作用。另外的体外放射自显影显示，[ 18 F]BIBD-399
• Antioxidant-Conjugated 1,2,4-Triazolo[4,3-<i>a</i>]pyrazin-3-one Derivatives: Highly Potent and Selective Human A_2A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain
  作者：Matteo Falsini、Daniela Catarzi、Flavia Varano、Costanza Ceni、Diego Dal Ben、Gabriella Marucci、Michela Buccioni、Rosaria Volpini、Lorenzo Di Cesare Mannelli、Elena Lucarini、Carla Ghelardini、Gianluca Bartolucci、Marta Menicatti、Vittoria Colotta

  DOI：10.1021/acs.jmedchem.9b00778

  日期：2019.9.26

  New 8-amino-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-ones were designed to obtain dual antioxidant-human A(2A) adenosine receptor (hA(2A) AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di-tertbut-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines (1-21) were potent and selective hA(2A) AR antagonists (K-i = 0.17-54.5 nM). Compounds 11, 15, and 21, featuring antioxidant moieties, and compound 12, lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative 15 and the (4-hydroxy-3,5-di-tertbutyl)benzoyl-analogue 21 which were effective in reducing the oxygen free radical level. The lipoyl-derivative 15 was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of 15 makes it a promising neuroprotective agent in oxidative stress-related diseases.
• The 1,2,4-Triazolo[4,3-<i>a</i>]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A_2A Receptor Subtype
  作者：Matteo Falsini、Lucia Squarcialupi、Daniela Catarzi、Flavia Varano、Marco Betti、Diego Dal Ben、Gabriella Marucci、Michela Buccioni、Rosaria Volpini、Teresa De Vita、Andrea Cavalli、Vittoria Colotta

  DOI：10.1021/acs.jmedchem.7b00457

  日期：2017.7.13

  In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin-3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R-6), was synthesized with the main purpose of targeting the hA(2A) adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA(2A) AR (K-i = 2.910 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA(2A) AR antagonist (12, R = H, R-6 = 4-methoxyphenyl) demonstrated some ability to counteract MPP+-induced neurotoxicity in cultured human neuroblastoma SH-SY5Y cells, a widely used in vitro Parkinsons disease model. Docking studies at hAR structures were performed to rationalize the observed affinity data.
• New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A2A adenosine receptor antagonists
  作者：Matteo Falsini、Costanza Ceni、Daniela Catarzi、Flavia Varano、Diego Dal Ben、Gabriella Marucci、Michela Buccioni、Aleix Martí Navia、Rosaria Volpini、Vittoria Colotta

  DOI：10.1016/j.bmcl.2020.127126

  日期：2020.6

  achieve potent and selective human A2A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1-9 and 10-18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like

  在这项工作中，对8-氨基-2-苯基-6-芳基-1,2,4-三唑并[4,3-a]吡嗪-3-one系列进行了进一步的结构研究，以实现有力和选择性的人A2A腺苷受体（AR）拮抗剂。不同的醚和酰胺部分连接在6-苯环的对位，因此分别得到化合物1-9和10-18。这些部分大多数包含末端碱性环（吡咯烷，吗啉，哌啶和取代的哌嗪），它们被认为具有良好的理化性质和药物样性质。带有酰胺连接基的化合物11-16对hA2A AR具有高亲和力和选择性（Ki ＝ 3.6-11.8nM）。与相对酰胺化合物相比，具有醚接头的衍生物1-9也优先靶向hA2A AR，但亲和力较低。对接研究