Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives as adenosine receptor antagonists: a preliminary receptor-driven SAR profile

A new series of triazolo-triazine differently substituted at the C5 and N7 positions have been synthesized and fully characterized at the four human adenosine receptor (AR) subtypes. In particular, at the N7 position have been introduced arylacetil or arylcarbamoyl moieties which gave good affinity at the A2B and A3 ARs, respectively, when utilized on the pyrazolo-triazolo-pyrimidine nucleus as reported by our group in the past [1]. In general, compounds with the free amino group at the 7 position showed good affinity at the A2A AR (range 18.3–96.5 nM), while the introduction of a phenylcarbamoyl moiety at the N7 position slightly increases the affinity at the hA3 adenosine receptors (range 311–633 nM) with respect to the unsubstituted derivatives. Anyway, the binding profile of synthesized compounds seems to be correlated to both the substitutions at the C5 and N7 positions. Regarding the A2B adenosine receptors, derivative with the free amino group at the 7 position resulted to be the most potent at the hA2B AR (EC50 3,420 nM) and could represent a starting point for searching new non-xanthine hA2B AR antagonists. A preliminary receptor-driven structure–activity relationship based on the recently published crystallographic structure of the hA2A AR has been provided.