title: 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.
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.
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste , Piazzale Europa 1, 34127 Trieste, Italy.
authors: Stephanie
authors: S
authors: Federico
authors: Antonella
authors: A
authors: Ciancetta
authors: Nicola
authors: N
authors: Porta
authors: Sara
authors: S
authors: Redenti
authors: Giorgia
authors: G
authors: Pastorin
authors: Barbara
authors: B
authors: Cacciari
authors: Karl Norbert
authors: KN
authors: Klotz
authors: Stefano
authors: S
authors: Moro
authors: Giampiero
authors: G
authors: Spalluto
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058915:Purinergic P1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C494034:1,2,4-triazolo(1,5-c)pyrimidine; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D014230:Triazoles