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

The structure-activity relationship (SAR) of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives related to ZM241385 as antagonists of the A2A adenosine receptor (AR) was explored through the synthesis of analogues substituted at the 5 position. The A2A 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 theA2AARand, in some cases, receptor subtype selectivity.