Scaffold Decoration at Positions 5 and 8 of 1,2,4-Triazolo1,5-cPyrimidines to Explore the Antagonist Profiling on Adenosine Receptors:A Preliminary Structure-Activity Relationship Study

摘要

The structure-activity relationship (SAR) of new 5,8-disubstituted-1,2,4-triazolo1,5-cpyrimidines 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-triazolo1,5-cpyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAR.