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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.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-24 , DOI: 10.1016/j.bmcl.2020.127126 Matteo Falsini 1 , Costanza Ceni 1 , Daniela Catarzi 1 , Flavia Varano 1 , Diego Dal Ben 2 , Gabriella Marucci 2 , Michela Buccioni 2 , Aleix Martí Navia 2 , Rosaria Volpini 2 , Vittoria Colotta 1
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-03-24 , DOI: 10.1016/j.bmcl.2020.127126 Matteo Falsini 1 , Costanza Ceni 1 , Daniela Catarzi 1 , Flavia Varano 1 , Diego Dal Ben 2 , Gabriella Marucci 2 , Michela Buccioni 2 , Aleix Martí Navia 2 , Rosaria Volpini 2 , Vittoria Colotta 1
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In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to 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 properties. Compounds 11-16, bearing the amide linker, possessed high affinity and selectivity for the hA2A AR (Ki = 3.6-11.8 nM). Also derivatives 1-9, featuring an ether linker, preferentially targeted the hA2A AR but with lower affinity, compared to those of the relative amide compounds. Docking studies, carried out at the hA2A AR binding site, highlighted some crucial ligand-receptor interactions, particularly those provided by the appended substituent whose nature deeply affected hA2A AR affinity.
中文翻译：
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。
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
更新日期：2020-04-20
中文翻译：
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。
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
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