Recent advances in the discovery of small-molecule inhibitors for inflammatory bowel disease therapy

Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent intestinal ulceration. The rising global incidence of IBD in recent years has increased disease burden and highlighted the urgent need for more effective and safer treatments. Small-molecule therapeutics targeting critical pathogenic pathways represent a rapidly advancing area of IBD drug development, offering the advantages of stronger target binding affinity, better specificity, and more favorable pharmacokinetic performance compared to conventional therapies. This review summarizes the progress made in IBD small-molecule drugs in the past 5 years, covering the association between related targets and IBD pathogenesis, a series of new compounds acting on distinct molecular targets, including those that have advanced recently to clinical trials as well as those demonstrating promising anti-IBD activity in preclinical studies. The targets include key proteins (BRD4, PDE4, NLRP3), kinases (JAK, RIPK, SIK, IRAK), and G protein-coupled receptors (CCR6, CXCR4). For preclinical compounds, we highlighted the key structural modification process and structure-activity relationship (SAR) studies, summarizing their anti-inflammatory and intestinal protective activities demonstrated in both in vitro and in vivo experiments. Overall, this review aims to facilitate the rational development of next-generation, more effective, and safer small-molecule therapeutics for IBD.