Scaffold Decoration at Positions 5 and 8 of 1,2,4-Triazolo[1,5-c]Pyrimidines to Explore the Antagonist Profiling on Adenosine Receptors: A Preliminary Structure-Activity Relationship Study

The structure-activity relationship (SAR) of new 5,8-disubstituted-1,2,4-triazolo[1,5-c]pyrimidines as adenosine receptors (ARs) antagonists has been explored. All the synthesized compounds show affinity for the hA(2A) and hA(3) ARs depending on the substitution patterns at the 5 and 8 positions. In particular, a free amino group at the 5 position with an ethoxycarbonyl group at the 8 position leads to potent and quite selective hA(2A) antagonists (compound 12: hA(2A) AR K-i = 3.32 nM; hA(1)/hA(2A) = 55.6; hA(2A)/hA(3) = 0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA(3) AR (compound 23: hA(3) AR K-i = 4.14 nM, hA(1)/hA(3) = 236; hA(2A)/hA(3) = 25). Through an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 and 8 positions of the 1,2,4-triazolo[1,5-c]pyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAP..