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

Authors

Xiao Liang, Xue Li, Junxin Xue, Huirui Wang, Huajun Zhao, Zhongcheng Zhao, Xinying Yang, Jintong Du, Ting Dong, Hao Fang, Xuben Hou

Published in

Journal of medicinal chemistry. Apr 27, 2026. Epub Apr 27, 2026.

Abstract

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.

PMID:
42046270
Bibliographic data and abstract were imported from PubMed on 28 Apr 2026.

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