Discovery of N-Substituted Acetamide Derivatives as Promising P2Y 14 R Antagonists Using Molecular Hybridization Based on Crystallographic Overlay.

P2Y 14 receptor (P2Y 14 R) is activated by uridine 5'-diphosphate-glucose, which is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y 14 R antagonists and the crystallographic overlap study between the reported P2Y 14 R antagonist compounds 6 and 9 , a series of N-substituted-acetamide derivatives were designed, synthesized, and identified as novel and potent P2Y 14 R antagonists. The most potent antagonist, compound I-17 ( N -(1 H -benzo[ d ]imidazol-6-yl)-2-(4-bromophenoxy)acetamide, IC 50 = 0.6 nM) without zwitterionic character, showed strong binding ability to P2Y 14 R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In vitro and in vivo evaluation demonstrated that compound I-17 had satisfactory inhibitory activity on the inflammatory response of monosodium urate (MSU)-induced acute gouty arthritis. I-17 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 I-17 , with potent P2Y 14 R antagonistic activity, in vitro and in vivo efficacy, and favorable bioavailability ( F = 75%), could be a promising lead compound for acute gouty arthritis.