2. Academic Validation
  3. Discovery of a series of novel 3-sulfonamido benzoic acid derivatives as promising P2Y14R antagonists for acute lung injury

Discovery of a series of novel 3-sulfonamido benzoic acid derivatives as promising P2Y14R antagonists for acute lung injury

  • Eur J Med Chem. 2025 Jun 5:290:117588. doi: 10.1016/j.ejmech.2025.117588.
Shiyu Ma 1,  Mingzhu Wang 2,  Yangang Wu 3,  Dian Meng 1,  Bin Zhang 2,  Hailiang Zhu 4,  Yongfang Yao 5,  Yongtao Duan 6,  Chuanjun Song 7
Affiliations

Affiliations

  • 1 College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China.
  • 2 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China.
  • 3 College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China.
  • 5 Pingyuan Laboratory, Zhengzhou, 450001, China; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China. Electronic address: yongfangyao@zzu.edu.cn.
  • 6 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China. Electronic address: duanyongtao860409@163.com.
  • 7 College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China. Electronic address: chjsong@zzu.edu.cn.
PMID: 40179611 DOI: 10.1016/j.ejmech.2025.117588
Abstract

The P2Y14 receptor (P2Y14R) has been identified as a potential target for various inflammatory diseases, particularly acute lung injury (ALI). However, very few P2Y14R antagonists have been reported so far, especially those with innovative scaffolds. And none have entered clinical trials due to the shortcomings of low antagonistic activity and poor druggability. Herein, we designed, synthesized and evaluated a series of 3-sulfonamido benzoic acid derivatives as P2Y14R antagonists with novel scaffolds based on PPTN, which is considered to be the most potent P2Y14R antagonist. Among them, compound 25l (IC50 = 5.6 ± 0.3 nM) emerged as the most potent P2Y14R antagonist, exhibiting not only significantly better antagonistic activity compared to the rest but also superior binding affinity to P2Y14R over PPTN. Moreover, the solubility and pharmacokinetic properties of compound 25l were proven to be better than those of PPTN. The anti-inflammatory effect of compound 25l was investigated using an LPS-induced mouse ALI model. The results showed that compound 25l significantly reduced the inflammatory response in lung tissues and the levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) induced by LPS. Therefore, compound 25l, with its potent P2Y14R antagonistic activity and favorable druggability, is a promising candidate for further investigation as an anti-inflammatory drug.

Keywords

3-Sulfonamido benzoic acid derivatives; Acute lung injury; Anti-inflammatory activity; P2Y(14) receptor antagonist.

Figures
Products