Regio- and Stereoselective Ribose Modification in Truncated 2,8-Disubstituted Adenosine Scaffold to Develop Highly Potent A Adenosine Receptor Antagonists.

Previous molecular dynamics simulations of hAAR with and structure-activity relationship (SAR) analyses prompted us to synthesize diol-, deoxy-, fluoro-, and methoxy-derivatives () in a regio- and stereoselective manner, modifying the ribose moiety to enhance potency and selectivity at hAAR. SAR analysis revealed that the presence of at least one hydroxyl group at either the R or R position is preferred for hAAR binding, and inversion of the R hydroxyl group significantly reduced binding affinity at hAAR. Alteration of the hydroxyl groups in the ribose moiety showed that hAAR favored diol derivatives, and the following trend was observed at hAAR: , diol ≈ deoxy < fluoro < methoxy. Among the synthesized derivatives, the deoxy derivative demonstrated exceptional potency at hAAR ( = 0.36 ± 0.05 nM) and functional efficacy. Additionally, exhibited promising pharmacokinetic properties, and efficacy assays confirmed its potential as an orally available immune checkpoint inhibitor candidate.