[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

• DOI: 10.1016/j.ejmech.2018.08.042
• Publication Date: 2018-08-20T05:57:31Z
• Authors: Stephanie Federico; Enrico Margiotta; Veronica Salmaso; Giorgia Pastorin; Sonja Kachler; Karl-Norbert Klotz; Stefano Moro; Giampiero Spalluto
• Keywords: Models, Molecular; Molecular modeling; Docking; Structure-Activity Relationship; 03 medical and health sciences; A3 antagonist; Humans; G protein-coupled receptor; Pharmacology; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Receptor, Adenosine A3; Adenosine receptor; A3 antagonist; Adenosine receptor; Docking; G protein-coupled receptor; Molecular modeling; [1,2,4]triazolo[1,5-c]pyrimidine; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Purinergic P1 Receptor Antagonists; Pyrimidines; Receptor, Adenosine A3; Structure-Activity Relationship; Triazoles; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Triazoles; 3. Good health; Pyrimidines; Pyrimidine; Purinergic P1 Receptor Antagonists; Purinergic P1 Receptor Antagonist; Triazole; [1,2,4]triazolo[1,5-c]pyrimidine; Human

[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.