Design and Synthesis of Novel sEH Inhibitors for the Treatment of Inflammatory Bowel Disease

Huashen Xu; Ruolin Cao; Xinyue Dong; Ruiyi Ma; Christophe Morisseau; Yuanguang Chen; Junning Zhuang; Fuqin Liu; Lu Chen; Maoying Zhang; Gaohua Wang; Zhongbo Liu; Bruce D Hammock; Guoliang Chen

doi:10.1021/acs.jmedchem.5c00854

Design and Synthesis of Novel sEH Inhibitors for the Treatment of Inflammatory Bowel Disease

J Med Chem. 2025 Jul 1. doi: 10.1021/acs.jmedchem.5c00854. Online ahead of print.

Authors

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
² School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California 95616, United States.
⁴ Department of Pharmacology, Hongshanhu Pharmaceutical Group Co., Ltd., Floor 10M, Building 4, Area 3, Hanwei International Plaza, Fengtai District, Beijing 100071, China.

PMID: 40590615
DOI: 10.1021/acs.jmedchem.5c00854

Abstract

The treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of immune inflammatory factors to reach a favorable therapeutic effect. In the current study, we discovered a series of sEH inhibitors containing a squaryl sulfonamide scaffold that potently inhibited the primary proinflammatory signaling pathways of NF-κB. Especially, lead compounds A1 and A9 showed potent inhibitory activities against sEH (A1 and A9; hsEH IC₅₀ = 0.1 nM, msEH IC₅₀ = 0.1 nM). The compound A1 had medium pharmacokinetic characteristics in rats. In vivo, A1 showed a strong anti-inflammatory activity in acute enteritis models and decreased the release of various proinflammatory factors, including IL-6 and TNF-α. More importantly, A1 maintained the integrity of the intestinal barrier. Besides, A1 possessed good in vivo tolerability in subacute safety evaluation. Collectively, this study provided valuable lead compounds for the treatment of IBD that were worthy of further development.