Synthesis and SAR studies of trisubstituted purinones as potent and selective adenosine A2A receptor antagonists

A series of trisubstituted purinones was synthesized and evaluated as A2A receptor antagonists. The A2A structure–activity relationships at the three substituted positions were studied and selectivity against the A1 receptor was investigated. One antagonist 12o exhibits a Ki of 9 nM in an A2A binding assay, a Kb of 18 nM in an A2A cAMP functional assay, and is 220-fold selective over the A1 receptor.

Graphical abstractA series of trisubstituted purinones was synthesized and evaluated as A2A receptor antagonists. The A2A structure–activity relationships at the three substituted positions were studied and selectivity against the A1 receptor was investigated.Figure optionsDownload full-size imageDownload as PowerPoint slide