Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: Effect of the N-5 bond type on the affinity and selectivity at the four adenosine receptor subtypes

In the last few years, many efforts have been made to search for potent and selective human A(3) adenosine antagonists. In particular, one of the most promising human A(3) adenosine receptor antagonists is represented by the pyrazolo-triazolo-pyrimidine family. This class of compounds has been strongly investigated from the point of view of structure-activity relationships. In particular, it has been observed that fundamental requisites for having both potency and selectivity at the human A(3) adenosine receptors are the presence of a small substituent at the N(8) position and an unsubstitued phenyl carbamoyl moiety at the N(5) position. In this study, we report the role of the N(5)-bond type on the affinity and selectivity at the four adenosine receptor subtypes. The observed structure-activity relationships of this class of antagonists are also exhaustively rationalized using the recently published ligand-based homology modeling approach.