Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective adenosine A2A receptor antagonists

SCH 58261 is a reported adenosine A2A receptor antagonist, which is active in rat in vivo models of Parkinson’s Disease upon ip administration. However, it has poor selectivity versus the A1 receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A2A receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A2A receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.

Graphical abstractThe design and synthesis of biaryl and heteroaryl analogs of the adenosine A2A receptor antagonist SCH 58261 are reported. Derivatives such as the quinoline 25 improve upon the pharmacological and pharmacokinetic properties of the parent phenethyl compound SCH 58261.Figure optionsDownload full-size imageDownload as PowerPoint slide