SPH7854, a gut-limited RORγt antagonist, ameliorates TNBS-induced experimental colitis in rat

• Published in: International immunopharmacology 2024-10, Vol.140, p.112884, Article 112884
• Main Authors: Xiang, Zhijun, Zhang, Bingbin, Cao, Shuangyi, Cao, Long, Li, Lingwen, huang, Dehua, Li, Qian, Chen, Yuxiang, Gong, Xuelian, Zhang, Xiaohong, Li, Ruizhi, Wu, Jinmiao, Peng, Yayuan, Huo, Guoyong, Xu, Lixia, Zhang, Zhihui, Li, Di, Xia, Guangxin
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Acetamides - therapeutic use; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cell Differentiation - drug effects; Cells, Cultured; Colitis; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Colon - drug effects; Colon - immunology; Colon - pathology; Disease Models, Animal; Gut-limited; Humans; IBD; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - metabolism; Male; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Rats; Rats, Sprague-Dawley; RORγt; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Th17; Th17 Cells - drug effects; Th17 Cells - immunology; Treg; Trinitrobenzenesulfonic Acid
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112884

[Display omitted] •The imbalance of Th17 cells/Treg cells in mucosa of gastrointestinal tract often results in the recruitment and activation of neutrophil and macrophage, as well as the release of pro-inflammatory cytokine or mediator, contributing the pathogenesis of IBD.•Modulation of the ratio of Th17 cells/Treg cells through blocking the activity of RORγt is a potential strategy for IBD treatment. However, the adverse sides of systemic blockade of RORγt hampered the clinical development of RORγt antagonist.•Gut-restricted drugs can achieve high local concentrations at the site of action while minimizing systemic exposure, lowering the safe risks arising from on- and off-target activity elsewhere in the body.•SPH7854, a gut-restricted RORγt selective antagonist, significantly ameliorated TNBS-induced murine colitis possibly through decreasing the Th17/Treg cell ratio and subsequently reducing the recruitment and activation of neutrophils and macrophages as well as the release of pro-inflammatory cytokines or mediators in mucosa of colon. Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trini