Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China.
J Med Chem. 2024 Jun 27;67(12):10233-10247. doi: 10.1021/acs.jmedchem.4c00555. Epub 2024 Jun 14.
P2Y receptor (P2YR) is activated by uridine 5'-diphosphate-glucose, which is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2YR antagonists and the crystallographic overlap study between the reported P2YR antagonist compounds and , a series of N-substituted-acetamide derivatives were designed, synthesized, and identified as novel and potent P2YR antagonists. The most potent antagonist, compound (-(1-benzo[]imidazol-6-yl)-2-(4-bromophenoxy)acetamide, IC = 0.6 nM) without zwitterionic character, showed strong binding ability to P2YR, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. and evaluation demonstrated that compound had satisfactory inhibitory activity on the inflammatory response of monosodium urate (MSU)-induced acute gouty arthritis. decreased inflammatory factor release and cell pyroptosis through the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway. Thus, compound , with potent P2YR antagonistic activity, and efficacy, and favorable bioavailability ( = 75%), could be a promising lead compound for acute gouty arthritis.
P2Y 受体（P2YR）被尿苷 5'-二磷酸葡萄糖激活，它参与了许多人类炎症性疾病。基于目前报道的 P2YR 拮抗剂的分子对接分析和报道的 P2YR 拮抗剂化合物 和 之间的晶体结构重叠研究，设计、合成并鉴定了一系列 N-取代乙酰胺衍生物，它们是新型有效的 P2YR 拮抗剂。最有效的拮抗剂，化合物 （-(1-苯并[]咪唑-6-基）-2-（4-溴苯氧基）乙酰胺，IC = 0.6 nM）没有两性离子特征，表现出对 P2YR 的强结合能力、高选择性、中等口服生物活性和改善的药代动力学特征。 和 评估表明，化合物 对尿酸单钠（MSU）诱导的急性痛风性关节炎的炎症反应具有令人满意的抑制活性。通过 NOD 样受体家族吡喃结构域包含 3（NLRP3）/gasdermin D（GSDMD）信号通路，化合物 减少了炎症因子的释放和细胞焦亡。因此，化合物 具有有效的 P2YR 拮抗活性、抗炎和抗痛风活性以及良好的生物利用度（=75%），可能是治疗急性痛风性关节炎的有前途的先导化合物。
