Design, Synthesis, and Biological Evaluation of 2-Arylaminopyrimidine Derivatives as Dual Cathepsin L and JAK Inhibitors for the Treatment of Acute Lung Injury

  • J Med Chem. 2025 Jan 9;68(1):361-386. doi: 10.1021/acs.jmedchem.4c02030.
Chunwei Shen  1 ,  Zhengtong Mao  1 ,  Tianpeng Chen  1 ,  Yingying Wei  2 ,  Tao Zhou  3 ,  Ningyuan Zhong  4 ,  Gaoyang Zhu  1 ,  Qiwen Shi  3 ,  Zheyu Xie  4 ,  Huajun Zhao  2 ,  Xingxian Zhang  1
Affiliations
  • 1. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China.
  • 2. College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, P. R. China.
  • 3. Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China.
  • 4. Shaoxing Institute for Food and Drug Control, Shaoxing, Zhejiang 312071, P. R. China.
PMID: 39699557 DOI: 10.1021/acs.jmedchem.4c02030
Abstract

Acute lung injury (ALI) is a disease characterized by pulmonary inflammation, blood barrier functional disorder, and hypoxemia. Herein, a series of 2-aminopyrimidine derivatives were synthesized. Most of them exhibited inhibitory effects on inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Compound A8 displayed an excellent anti-inflammatory activity, achieving inhibition rates of 83% for IL-6 and 85% for IL-8. Besides, A8 has a strong binding affinity to CTSL and a good inhibitory activity on JAKs. Western blot analysis indicated that compound A8 strongly blocked the maturation of CTSL and the phosphorylation of p-38, p-65, and STATs, thereby repressing the activation of the MAPK, NF-κB, and JAK/STAT signaling pathway. Moreover, animal experiments showed that A8 played a protective and therapeutic role in ALI in mice, validating its potential as a treatment for ALI.

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