Pyrazolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine template: Organic and medicinal chemistry approach

A medicinal chem. approach on the synthesis of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and related compds. is reported. This method permits the completion of the SAR anal. on this class of chem. mols. Evaluating their pharmacol. profiles, several structural modifications to modulate the biol. activity vs. the different adenosine receptor subtypes was planned. These efforts led to the discovery of a variety of selective antagonists for the A2A and A3 receptors, performing modifications at the N7,N8,N5,C9,C2-position of the pyrazolo-triazolo-pyrimidine core and by the replacement of the 2-(2-furyl)[1,2,4]triazole mol. part with substituted 2-thioxotriazole, dioxotriazine, oxotriazine, and 1,2,4-triazepine moieties. Modifications at the N7-pyrazole performed by the introduction of different alkyl or arylalkyl chains, led to the discovery of very potent and selective A2A receptor antagonists, whereas, functionalization at the N5-position together with the modulation of the pattern of substitution on the N8-pyrazole nitrogen revealed new A3 antagonists suitable to represent candidate for the pharmacol. and clin. investigations. Other modifications performed to the tricyclic nucleus, such as the introduction at the C9-position of thioethyl, aminoalkyl and (cyclo)alkylamino radicals and the replacement of a 2-furyl moiety with substituted arom. rings led to a diminished receptor affinity. Also the replacement of the 2-(2-furyl)triazolo template with new heterocycles revealed inactive mols. but led to an understanding of which structural modifications introduced on the pyrazolo-triazolo-pyrimidine structure played an important role on ligand-receptor interaction. In this way, it was noticed which position of the heterocyclic structure is not allowed to be modified and, on the contrary, what position is susceptible to modification or functionalization.