Selective and potent adenosine A3 receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold

The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A3 adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (Ki on A3 AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A3AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure–activity and structure–selectivity relationships in this series.

Graphical abstractDiverse methoxyphenyl substitutions on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold have been explored through a collaborative computational and synthetic effort, characterizing and rationalizing their enhanced potency and selectivity on the human adenosine A3 receptor.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel 2,6-diaryl-4-acetamidopyrimidines were obtained. ► Three compounds exhibit low nanomolar Ki values. ► Potent and selective A3 adenosine receptor antagonists were identified. ► A putative binding mode for the compounds prepared was proposed.