HQL6 serves as a novel P2Y receptor antagonist to ameliorate acute gouty arthritis through inhibiting macrophage pyroptosis.

Acute gouty arthritis (AGA) has been classified as an autoinflammatory disease caused by deposition of monosodium urate crystals (MSU), accompanied by swellingofjoint and severe pain. Limited clinical therapy and highincidence indicate that the development of effective drugs for AGA is an urgent need. Our previous study found that P2Y receptor (P2YR) was a potential target in anti-gout treatment through regulating pyroptosis of macrophages under exposure of MSU. Based on previous work, we carried out further structure modifications and led to a more effective antagonist HQL6 with IC of 3.007 nM. Extensive profiling of HQL6 has demonstrated that its high selectivity, good pharmacokinetic properties, and reliable in vivo anti-gout efficacy. Moreover, P2YR has been demonstrated to be the key target of HQL6 since the diminished effects on adenylate cyclase inhibitor-induced acute gouty arthritis in P2YR knockout rats. More importantly, results of single point mutant experiments exhibited that HQL6 might interact with Lys277 as favorable residue in the binding pocket of P2YR. Therefore, we confirmed that P2YR was a promising drug target for AGA, and HQL6 would be an available candidate for further drug development.