Discovery of N-Substituted Acetamide Derivatives as Promising P2Y14R Antagonists Using Molecular Hybridization Based on Crystallographic Overlay

  • J Med Chem. 2024 Jun 27;67(12):10233-10247. doi: 10.1021/acs.jmedchem.4c00555.
Wenjin Liu  1  2 ,  Shuqiang Mao  3 ,  Yuyang Wang  1 ,  Mingzhu Wang  1 ,  Mengyu Li  2 ,  Moran Sun  2 ,  Yongfang Yao  2  4 ,  Chuanjun Song  3  4 ,  Yongtao Duan  1
Affiliations
  • 1. Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
  • 2. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China.
  • 3. College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
  • 4. Pingyuan Laboratory, Zhengzhou University, Zhengzhou 450001, China.
PMID: 38874515 DOI: 10.1021/acs.jmedchem.4c00555
Abstract

P2Y14 receptor (P2Y14R) is activated by uridine 5'-diphosphate-glucose, which is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y14R antagonists and the crystallographic overlap study between the reported P2Y14R antagonist compounds 6 and 9, a series of N-substituted-acetamide derivatives were designed, synthesized, and identified as novel and potent P2Y14R antagonists. The most potent antagonist, compound I-17 (N-(1H-benzo[d]imidazol-6-yl)-2-(4-bromophenoxy)acetamide, IC50 = 0.6 nM) without zwitterionic character, showed strong binding ability to P2Y14R, 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 P2Y14R antagonistic activity, in vitro and in vivo efficacy, and favorable bioavailability (F = 75%), could be a promising lead compound for acute gouty arthritis.

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