Design, Synthesis, Activity Evaluation and Molecular Docking Study of Novel Janus kinase Inhibitors

Abstract

AbstractJanus kinase (JAK) is a non receptor tyrosine protein kinase, which has attracted wide attention and JAK inhibitors are mainly used to screen therapeutic drugs for hematological diseases, tumors, rheumatoid arthritis (RA) and psoriasis. Filgotinib is an oral small molecule JAK inhibitor which is currently at the clinical stage to treat Crohn's disease (CD) and rheumatoid arthritis. In this study, we designed novel triazolopyridine derivatives A1–A4 using Filgotinib as the lead compound, then replaced cyclopropane with trifluoromethane and replaced triazolopyridine with imidazopyrazine to get B1–B4 by isosteric principle of bioelectronics. These compounds were prepared in this work, and the corresponding effects against JAK1, JAK2 and JAK3 were assessed. The results indicated that B2 had stronger inhibitory effect on JAK1 and JAK3. A1 and A2 showed a good inhibitory effect on JAK1. Molecular docking results showed that compounds A1, A2 and B2 bind well to protein binding sites. These compounds can supply leading compounds for developing rheumatoid arthritis and Crohn's drugs.