Discovery of Benzofuran-2-Carboxylic Acid Derivatives as Potent PTPRO Inhibitors with Oral Efficacy for Treatment of Inflammatory Bowel Disease.

Emerging evidence implicates PTPRO as a pivotal regulator in inflammatory bowel disease (IBD). Screening a benzofuran-2-carboxylic acid-based library identified a lead PTPRO inhibitor. Structure-guided optimization yielded compound 10j, a potent and selective PTPRO inhibitor (IC50 = 0.54 μM) that suppressed IL-6 via NF-κB pathway modulation in macrophages. Compound 10j exhibited favorable oral bioavailability and, in a murine DSS-induced colitis model, significantly attenuated disease severity, restored colon length, and suppressed IFN-γ and IL-2 levels. Further optimization produced 30k with enhanced potency (IC50 = 0.16 μM) and superior in vivo efficacy accompanied by an improved safety profile. This work establishes benzofuran-2-carboxylic acid derivatives as promising IBD therapeutics, providing a pharmacological tool for phosphatase-targeted immunomodulation.