Discovery ofa Novel P2X2/3 Allosteric Antagonistas an Efficient Bitter Taste Blocker

Abstract Masking the taste of unpalatable medicines is a key approach to improving treatment compliance, especially with children, where this issue is exacerbated. The P2X2/3 purinergic receptor is a ligand-gated ion channel activated by ATP that relays information from taste cells to the brain. Inhibition of this receptor has been demonstrated to block taste perception in humans and mice, suggesting that the application of a potent and short-lived antagonist directly on the tongue could provide a solution to improve treatment compliance. The previously reported dual P2X3 and P2X2/3 antagonist AF-353 (1) was used as a starting point for our campaign. A novel pyrazolopyrimidine core was identified using a scaffold-hopping strategy, which delivered compound 30 after SAR optimization. This novel antagonist displayed very high activity against P2X2/3, combined with desired physicochemical properties, resulting in a more efficacious taste-blocking effect in mice when compared to AF-353 (1).