Structure-guided design of potent JAK1-selective inhibitors based on 4-amino-7H-pyrrolo[2,3-d]pyrimidine with anti-inflammatory efficacy.

In a continuous effort to develop Janus kinase 1 (JAK1)-selective inhibitors, a novel series of 4-amino-7H-pyrrolo[2,3-d]pyrimidine derivatives bearing the piperidinyl fragment were designed and synthesized according to a combination strategy. Through enzymatic assessments, the superior compound 12a with an IC50 value of 12.6 nM against JAK1 was identified and a 10.7-fold selectivity index over JAK2 was achieved. It was indicated that 12a displayed considerable effect in inhibiting the pro-inflammatory NO generated from lipopolysaccharide (LPS)-induced RAW264.7 macrophages, while on normal RAW264.7 cells, 12a exerted a weak cytotoxicity effect (IC50 = 143.3 μM). Furthermore, H&E stain assay demonstrated the conspicuous capacity of 12a to suppress CCl4-induced hepatic fibrosis levels in a dose-dependent manner in vivo. The binding model of 12a ideally reflects the excellent activity of JAK1 over the homologous kinase JAK2. Overall, 12a, a JAK1-selective inhibitor, exhibited potential for liver fibrosis and inflammatory diseases.