3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: A Novel Template for the Design of Highly Selective A2B Adenosine Receptor Antagonists

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• 作者：Sabrina Taliani ; Isabella Pugliesi ; Elisabetta Barresi ; Francesca Simorini ; Silvia Salerno ; Concettina La Motta ; Anna Maria Marini ; Barbara Cosimelli ; Sandro Cosconati ; Salvatore Di Maro ; Luciana Marinelli ; Simona Daniele ; Maria Letizia Trincavelli ; Giovanni Greco ; Ettore Novellino ; Claudia Martini ; Federico Da Settimo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 23, 2012
• 年：2012
• 卷：55
• 期：4
• 页码：1490-1499
• 全文大小：470K
• 年卷期：v.55,no.4(February 23, 2012)
• ISSN：1520-4804

文摘

In an effort to identify novel ligands possessing high affinity and selectivity for the A_2B AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A₁ AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our 鈥渋n-house鈥?collection revealed that all the derivatives selected showed significant affinity at A_2B AR, no affinity at A₃ AR, and various degrees of selectivity toward A₁ and A_2A ARs. Investigation of a new series featuring modified substituents at the 10-position (4鈥?chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A_2B AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A_2A AR, conferring high A_2B/A_2A AR selectivity. Derivative 13 (X = Cl, R = C₆H₅) is the most potent and selective compound, with an IC₅₀ of 3.10 nM at A_2B AR and no affinity at A₁, A_2A, and A₃ ARs.