Synthesis and Biological Evaluation of a New Series of 124-triazolo15-a-135-triazines as Human A2A Adenosine Receptor Antagonists with Improved Water Solubility

摘要

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 the A2A 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 (Ki 11.5 nM) and its urethane-protected derivative >14 (Ki 17.8 nM). Compounds >20 and >31 (Ki 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 hA2A 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.