2. Academic Validation
  3. Discovery of a potent, Highly selective, and In vivo anti-inflammatory Efficacious, P2Y6R antagonist with a novel quinoline-pyrazole scaffold

Discovery of a potent, Highly selective, and In vivo anti-inflammatory Efficacious, P2Y6R antagonist with a novel quinoline-pyrazole scaffold

  • Eur J Med Chem. 2024 Sep 23:279:116890. doi: 10.1016/j.ejmech.2024.116890.
Yabiao Zhao 1,  Bingqian Han 2,  Zhiyi Wei 1,  Yuanzhe Li 3,  Yongfang Yao 4,  Chuanjun Song 5,  Yongtao Duan 6
Affiliations

Affiliations

  • 1 College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China.
  • 2 School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
  • 3 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China.
  • 4 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, Henan, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China. Electronic address: yongfangyao@zzu.edu.cn.
  • 5 College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China. Electronic address: chjsong@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.
PMID: 39341096 DOI: 10.1016/j.ejmech.2024.116890
Abstract

The P2Y6 receptor (P2Y6R), as a crucial member of the purine family, is a potential therapeutic target for the treatment of intestinal inflammation, tracheal inflammation and diabetes. We first discovered the hit compound (5a, IC50 = 168.5 nM against P2Y6R) through our in-house library screening. Then, further medicinal chemistry efforts were made to optimize compound 5a, and a potent P2Y6R antagonist (5 ab) with better antagonistic activity (IC50 = 19.6 nM) was obtained. The molecular docking, CETSA, SPR and pull-down results indicated that compound 5 ab displayed strong binding to P2Y6R. Also, compound 5 ab possessed high selectivity and satisfying oral bioactivity and pharmacokinetic profiles. In experiments with LPS-induced acute lung injury in mice, after treatment with compound 5 ab, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased, the infiltration of immune cells was decreased. Further exploration revealed that 5 ab inhibited the expression and release of chemokines in lung tissue, suppressing the activation of the NLRP3 inflammasome. Compound 5 ab had certain anti-inflammatory abilities in vivo and in vitro. These results demonstrate that compound 5 ab is a potential P2Y6R antagonist and is worthy of further study.

Keywords

ALI; Anti-inflammatory; P2Y(6)R antagonist; Purine.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z