Abstract

JAK1 represents a clinically validated target for inflammatory bowel disease (IBD), but the safety concerns associated with systemic JAK1 inhibition remain unaddressed. In this study, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as novel, gut-restricted, selective JAK1 inhibitors for the treatment of IBD to mitigate potential systemic side effects. Among them, compound 38 exhibited potent JAK1 inhibition (IC50 < 0.5 nM) and robust cellular potency (IC50 = 28 nM) in the JAK/STAT signaling pathway. It also demonstrated remarkable selectivity over JAK2 (>312-fold), JAK3 (>20,000-fold), and TYK2 (>354-fold), respectively. Furthermore, compound 38 displayed high intestinal exposure but low systemic exposure (<1 ng/mL) in mice, confirming its gut-restricted nature. In a DSS-induced colitis model, compound 38 significantly ameliorated inflammatory symptoms, promoted epithelial repair, and suppressed the production of proinflammatory cytokines (e.g., TNF-α and IL-6). Thus, compound 38 was identified as a therapeutically promising candidate compound for treating IBD.