Discovery of Selective P2Y 6 R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy.

As a member of purinoceptors, the P2Y receptor (P2YR) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2YR, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2YR antagonist (compound ) was identified to possess excellent antagonistic activity (IC = 5.914 nM) and high selectivity. In addition, binding assays and chemical pull-down experiments confirmed that compound was nicely bound to P2YR. Notably, compound could effectively ameliorate DSS-induced ulcerative colitis in mice through inhibiting the activation of NLRP3 inflammasome in colon tissues. Moreover, treatment with compound reduced LPS-induced pulmonary edema and infiltration of inflammatory cells in mice. These findings suggest that compound could serve as a specific P2YR antagonist for treating inflammatory diseases and deserve further optimization studies.