Identification of Pyrrolo [2,3-b] Pyridine Derivatives as Novel JAK1 Inhibitors for the Treatment of Inflammatory Bowel Disease.

Treatment of inflammatory bowel disease (IBD) remains a major medical challenge due to the lack of safe and effective therapeutic agents. JAK1 has been validated as a key therapeutic target that modulates the pathological progression of IBD. In this study, using tofacitinib as the lead compound, we adopted a scaffold growth strategy to design and synthesize a series of pyrrolo [2,3-b] pyridine derivatives as novel JAK1 inhibitors for the treatment of IBD. Among them, compound 15 exerted potent inhibitory activity against JAK1 with an IC50 value of 0.48 nM. Western blot results showed that compound 15 significantly inhibited LPS-induced STAT1/3 phosphorylation in RAW264.7 cells. In addition, 15 exhibited satisfactory metabolic stability and oral bioavailability. In the DSS-induced colitis model, 15 remarkably ameliorated inflammatory symptoms, promoted epithelial repair, and inhibited the production of pro-inflammatory cytokines such as TNF-α and IL-6. Therefore, compound 15 is regarded as a promising candidate for the treatment of IBD.