Discovery of N-(6-Acetylpyridin-3-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide derivatives as a novel series of selective RORγt antagonists

  • Eur J Med Chem. 2026 Jun 26:317:119106. doi: 10.1016/j.ejmech.2026.119106.
Bingbin Zhang  1 ,  Zhuo Li  2 ,  Di Li  1 ,  Zhijun Xiang  3 ,  Guoyong Huo  1 ,  Chen Shi  1 ,  Lingjun Duan  1 ,  Yayuan Peng  1 ,  Long Cao  1 ,  Shuangyi Cao  1 ,  Lingwen Li  1 ,  Qian Li  1 ,  Jin Huang  3 ,  Dongmei Zhao  4 ,  Guangxin Xia  5
Affiliations
  • 1. Central Research Institute, State Key Laboratory of Innovative Immunotherapy, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, PR China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 3. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China.
  • 4. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: [email protected].
  • 5. Central Research Institute, State Key Laboratory of Innovative Immunotherapy, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, PR China. Electronic address: [email protected].
PMID: 42398399 DOI: 10.1016/j.ejmech.2026.119106
Abstract

The retinoic acid receptor-related Orphan Receptor gamma t (RORγt) is a member of the Nuclear Receptor Superfamily, expressed in lymphoid cells and driving Th17 cell differentiation and IL-17 production. The IL-17/IL-23 pathway is implicated in autoimmune and inflammatory diseases, such as inflammatory bowel disease (IBD). Targeting RORγt is considered a therapeutic intervention to suppress inflammation. Herein, we designed and synthesized a novel class of highly selective RORγt antagonists through scaffold-hopping and structure-activity relationship studies. Compound 14 (SPH7854) emerged as a preclinical candidate on the basis of its potent activity and favorable drug-like properties. SPH7854 demonstrated potent activity in preclinical models of inflammatory bowel disease and has advanced to clinical trials.

Keywords
Inflammatory bowel disease; RORγt antagonist; Safe drugs.
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