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

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.