Synthesis and Biological Evaluation of a New Series of 1,2,4-Triazolo[1,5-a]-1,3,5-triazines as Human A2A Adenosine Receptor Antagonists with Improved Water Solubility

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• 作者：Stephanie Federico ; Silvia Paoletta ; Siew Lee Cheong ; Giorgia Pastorin ; Barbara Cacciari ; Stefano Stragliotto ; Karl Norbert Klotz ; Jeffrey Siegel ; Zhan-Guo Gao ; Kenneth A. Jacobson ; Stefano Moro ; Giampiero Spalluto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 10, 2011
• 年：2011
• 卷：54
• 期：3
• 页码：877-889
• 全文大小：1204K
• 年卷期：v.54,no.3(February 10, 2011)
• ISSN：1520-4804

文摘

The structure鈭抋ctivity relationship (SAR) of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives related to ZM241385 as antagonists of the A_2A adenosine receptor (AR) was explored through the synthesis of analogues substituted at the 5 position. The A_2A AR X-ray structure was used to propose a structural basis for the activity and selectivity of the analogues and to direct the synthetic design strategy to provide access to solvent-exposed regions. Thus, we have identified a point of substitution for the attachment of solubilizing groups to enhance both aqueous solubility and physicochemical properties, maintaining potent interactions with the A_2A AR and, in some cases, receptor subtype selectivity. Among the most potent and selective novel compounds were a long-chain ether-containing amine congener 20 (K_i 11.5 nM) and its urethane-protected derivative 14 (K_i 17.8 nM). Compounds 20 and 31 (K_i 11.5 and 16.9 nM, respectively) were readily water-soluble up to 10 mM. The analogues were docked in the crystallographic structure of the hA_2A AR and in a homology model of the hA₃ AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed.