[1,2,4]Triazolo[1,5-c]pyrimidines as adenosine receptor antagonists: Modifications at the 8 position to reach selectivity towards A3 adenosine receptor subtype.
[1,2,4]Triazolo[1,5-c]pyrimidine is a promising platform to develop adenosine receptor antagonists. Here, we tried to investigate the effect of the substituent at the 8 position of [1,2,4]triazolo[1,5-c]pyrimidine derivatives on affinity and selectivity at the human A3 adenosine receptor subtype. In particular, we have introduced both esters and amides, principally with a benzylic nature. In addition, a small series of 5-substituted [1,2,4]triazolo[1,5-c]pyrimidines was designed in order to complete the structure-activity relationship analysis. Several of these new compounds showed affinity towards human A3 adenosine receptor in the low nanomolar range, with the most potent derivative of the series bringing a 4-ethylbenzylester at the 8 position (compound 18, hA3AR Ki = 1.21 nM). Docking studies performed on the synthesized compounds inside models of human A1, A2A and A3 adenosine receptors showed similar binding modes, comparable with the typical crystallographic binding mode of the inverse agonist ZM-241,385.
['Federico|Stephanie|S|', 'Margiotta|Enrico|E|', 'Salmaso|Veronica|V|', 'Pastorin|Giorgia|G|', 'Kachler|Sonja|S|', 'Klotz|Karl-Norbert|KN|', 'Moro|Stefano|S|', 'Spalluto|Giampiero|G|']
D004305:Dose-Response Relationship, Drug D006801:Humans D008958:Models, Molecular D015394:Molecular Structure D058915:Purinergic P1 Receptor Antagonists D011743:Pyrimidines D043684:Receptor, Adenosine A3 D013329:Structure-Activity Relationship D014230:Triazoles
[1,2,4]triazolo[1,5-c]pyrimidine Adenosine receptor Docking A(3) antagonist G protein-coupled receptor Molecular modeling