The P2Y2 receptor is a G protein-coupled receptor activated by extracellular nucleotides, is implicated in various pathologies, including cancer and inflammatory diseases. Despite its therapeutic relevance, potent and selective P2Y2R antagonists remain limited. Here, we report a comprehensive structure–activity relationship (SAR) study based on the clinical tool compound AR-C118925, aiming to enhance P2Y2R selectivity and drug-like properties through bioisosteric replacement of the tetrazole moiety via late-stage diversification. A diverse library of over 60 derivatives was synthesized and evaluated in Ca2+-flux assays. Multiple bioisosteres, including isoquinolinone and quinolinone scaffolds, retained or improved P2Y2R antagonistic potency while mitigating off-target activity, especially at P2X receptors. The most potent compound, 32g, demonstrated nanomolar potency (pIC50 = 7.78 ± 0.13) and high selectivity over other P2X subtypes. Structure-based modeling provided insights into ligand–receptor interactions guiding antagonistic potency. Collectively, these results provide a valuable scaffold for the development of selective and orally bioavailable P2Y2R antagonists.