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

Abstract

The structure-activity relationship (SARof 1, 2, 4-triazolo[1, 5-a]-1, 3, 5-triazine derivatives related to ZM241385 as antagonists of the A 2A adenosine receptor (ARwas 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 nMand its urethane-protected derivative 14 (K i 17.8 nM). Compounds 20 and 31 (K i 11.5 and 16.9 nM, respectivelywere readily water-soluble up to 10 mM. The analogues were docked in the crystallographic structure of the hA 2A AR andina homology model of the hA 3 AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed. © 2011 American Chemical Society