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Discovery of N-Substituted Acetamide Derivatives as Promising P2Y14R Antagonists Using Molecular Hybridization Based on Crystallographic Overlay.
Liu, Wenjin; Mao, Shuqiang; Wang, Yuyang; Wang, Mingzhu; Li, Mengyu; Sun, Moran; Yao, Yongfang; Song, Chuanjun; Duan, Yongtao.
Afiliação
  • Liu W; Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
  • Mao S; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China.
  • Wang Y; College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
  • Wang M; Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
  • Li M; Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
  • Sun M; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China.
  • Yao Y; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China.
  • Song C; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China.
  • Duan Y; Pingyuan Laboratory, Zhengzhou University, Zhengzhou 450001, China.
J Med Chem ; 67(12): 10233-10247, 2024 Jun 27.
Article em En | MEDLINE | ID: mdl-38874515
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores Purinérgicos P2 / Simulação de Acoplamento Molecular / Acetamidas Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores Purinérgicos P2 / Simulação de Acoplamento Molecular / Acetamidas Idioma: En Ano de publicação: 2024 Tipo de documento: Article