Acute gouty arthritis (AGA) has been classified as an autoinflammatory disease caused by deposition of monosodium urate crystals (MSU), accompanied by swelling of joint and severe pain. Limited clinical therapy and high incidence indicate that the development of effective drugs for AGA is an urgent need. Our previous study found that P2Y₁₄ receptor (P2Y₁₄R) 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 IC₅₀ 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, P2Y₁₄R has been demonstrated to be the key target of HQL6 since the diminished effects on adenylate cyclase inhibitor-induced acute gouty arthritis in P2Y₁₄R 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 P2Y₁₄R. Therefore, we confirmed that P2Y₁₄R was a promising drug target for AGA, and HQL6 would be an available candidate for further drug development.

急性痛风性关节炎（AGA）被归类为由单钠尿酸盐结晶（MSU）沉积引起的自身炎症性疾病，伴有关节肿胀 和 剧烈疼痛。有限的临床治疗和高 发病率表明，迫切需要开发有效的 AGA 药物。我们之前的研究发现，P2Y ₁₄受体（P2Y ₁₄ R）通过调节MSU暴露下巨噬细胞的焦亡，是抗痛风治疗的潜在靶点。基于之前的工作，我们进行了进一步的结构修饰，并产生了更有效的 IC _{50拮抗剂 HQL6}3.007 纳米。HQL6 的广泛分析表明其具有高选择性、良好的药代动力学特性和可靠的体内抗痛风功效。此外，P2Y ₁₄ R 已被证明是 HQL6 的关键靶标，因为 P2Y ₁₄ R 基因敲除大鼠对腺苷酸环化酶抑制剂诱导的急性痛风性关节炎的影响减弱。更重要的是，单点突变实验的结果表明，HQL6 可能与 Lys277 相互作用，作为 P2Y ₁₄ R 结合口袋中的有利残基。因此，我们证实 P2Y ₁₄ R 是 AGA 的一个有希望的药物靶点，HQL6 将是一个可用的进一步药物开发的候选者。