Pyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one as a New Scaffold To Develop Potent and Selective Human A3 Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluati

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• 作者：Vittoria Colotta ; Ombretta Lenzi ; Daniela Catarzi ; Flavia Varano ; Guido Filacchioni ; Claudia Martini ; Letizia Trincavelli ; Osele Ciampi ; Anna Maria Pugliese ; Chiara Traini ; Felicita Pedata ; Erika Mori
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2407-2419
• 全文大小：301K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

The paper describes a new class of human (h) A₃ adenosine receptor antagonists, the 2-arylpyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one derivatives (PTP), either 4-oxo (1−6, series A) or 4-amino-substituted (7−20, series B). In both series A and B, substituents able to act as hydrogen bond acceptors (OMe, OH, F, COOEt) were inserted on the 2-phenyl ring. In series B, cycloalkyl and acyl residues were introduced on the 4-amino group. Some of the new derivatives showed high hA₃ AR affinities (K_i < 50 nM) and selectivities vs both hA₁ and hA_2A receptors. The selected 4-benzoylamino-2-(4-methoxyphenyl)pyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one (18), tested in an in vitro rat model of cerebral ischemia, proved to be effective in preventing the failure of synaptic activity induced by oxygen and glucose deprivation in the hippocampus. Molecular docking of this new class of hA₃ AR antagonists was carried out to depict their hypothetical binding mode to our refined model of hA₃ receptor.