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 hA2A and hA3 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 hA2A antagonists (compound 12: hA2A AR Ki=3.32 nM; hA1/hA2A=55.6; hA2A/hA3=0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA3 AR (compound 23: hA3 AR Ki=4.14 nM, hA1/hA3=236; hA2A/hA3=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 SAR.

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

CACCIARI, Barbara;
2014

Abstract

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 hA2A and hA3 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 hA2A antagonists (compound 12: hA2A AR Ki=3.32 nM; hA1/hA2A=55.6; hA2A/hA3=0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA3 AR (compound 23: hA3 AR Ki=4.14 nM, hA1/hA3=236; hA2A/hA3=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 SAR.
Federico, Stephanie; Ciancetta, Antonella; Porta, Nicola; Redenti, Sara; Pastorin, Giorgia; Cacciari, Barbara; Klotz, Karl Norbert; Moro, Stefano; Spalluto, Giampiero
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11392/2331921
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