Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and linked heterocycles as template for the adenosine receptor antagonism: medicinal chemistry approach and SAR considerations.

The org. and medicinal chem. approach on the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and related compds. have permitted to complete the SAR evaluation on this class of mols. Planning several structural modifications, efforts made by our research group allowed the discovery of a variety of selective antagonists for the human A2A and A3 receptors, and in particular, chem. adaptations introduced at the N7-, N8-, N5-, C9-, C2-positions of the pyrazolo-triazolo-pyrimidine core revealed new potent and selective pharmacol. candidates. Modifications at the N7-pyrazole nitrogen performed by the introduction of different alkyl or arylalkyl chains, led to the discovery of very potent and selective A2A receptor antagonists. Otherwise different functionalisations at the N5-position together with modulation of the pattern of substitution on the N8-pyrazole nitrogen revealed new A3 antagonists suitable to represent new tools for the pharmacol. investigations. Other modifications performed to the tricyclic nucleus, such as the introduction at the C9-position of short thioalkyl, aminoalkyl and (cyclo)alkylamino radicals and the replacement of the 2-(2-furyl)[1,2,4]triazole mol. fragment with substituted 2-thioxotriazole, dioxotriazine, oxotriazine moieties led to a diminished receptor affinity and/or selectivity but allowed us to really understand which structural modifications introduced on the pyrazolo-triazolo-pyrimidine structure played an important role on ligand-receptor interaction.