P2Y14R antagonist 1 (compound I-17) is a potent and selective antagonist of the P2Y14 receptor, exhibiting an IC50 of 0.6 nM. This compound demonstrates robust anti-P2Y14R activity, effectiveness both in vitro and in vivo, and favorable pharmacokinetic properties. Additionally, P2Y14R antagonist 1 reduces the release of inflammatory mediators and cell pyroptosis through the NOD-like receptor family pyrin domain containing 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway. It shows promise for research in the field of acute gouty arthritis.

P2Y6 Receptor:89.7 nM, P2Y14 Receptor:0.6 nM, P2Y12 Receptor:> 100 nM, P2Y1 Receptor:> 100 nM, P2Y2 Receptor:> 100 nM

P2Y14R antagonist 1（compound I-17）在2-256 μM浓度范围内，经过24小时的处理后，未在RAW264.7细胞中显示出显著的细胞毒性。此外，当浓度为10-40 μM且作用时间为1小时时，P2Y14R antagonist 1能够抑制由Uric acid sodium和Lipopolysaccharides引起的痛风性炎症。同一浓度和时间条件下，该化合物还可抑制NLRP3炎症小体的组装及其上游过程，从而阻断caspase-1的激活和巨噬细胞的焦亡。

P2Y14R拮抗剂1（化合物I-17）（5-20 mg/mL，腹腔注射，注射时间60分钟）在Uric acid sodium诱导的小鼠痛风模型中表现出显著的抗炎作用。在这一研究中，化合物I-17显著减少了由Uric acid sodium晶体引起的小鼠足部肿胀，显著降低了由MSU诱导的促炎细胞因子IL-1β, IL-6和IL-18的产生，有效抑制了MSU诱导的足组织中炎性细胞浸润，并显著抑制了MSU引起的NLRP3的增加。