Discovery of uracil-based antagonists and fluorescent ligands of the P2Y2 receptor.

Antagonism of purinergic P2Y2 receptors offers potential benefits in the treatment of inflammatory diseases, neurodegenerative disorders, and cancer. Despite the promising preclinical potential, only a limited number of potent and selective non-nucleotide P2Y2R antagonists are known, including AR-C118925, which has been extensively used to study inhibition of the P2Y2R. However, unfavorable physicochemical properties and the presence of a reactive and photo-unstable 4-thiouracil moiety have limited their preclinical progress. Through a fragment recombination approach utilizing P2Y2R privileged fragments to explore non-additive SAR trends in combination with molecular docking studies, we discovered a series of potent uracil-based P2Y2R antagonists, such as compound 26a (pKi (whole cells) 6.55 ± 0.05). Molecular docking of 26a led to rationalization of the unexpected affinity for 26a, and led to the identification of new stable, uracil-based fluorescent ligands targeting the P2Y2R.