Identification of an Orally Bioavailable Quinoline-Based Small-Molecule Tumor Necrosis Factor α (TNF-α) Inhibitor Featuring a Spirocyclic Scaffold

  • J Med Chem. 2026 Apr 23;69(8):8987-9008. doi: 10.1021/acs.jmedchem.5c03457.
Zeren Sun  1  2 ,  Wenbin Zhang  2 ,  Wanyong He  2 ,  Jie Xu  2 ,  Boning Wang  2 ,  Joshua M He  3 ,  Yuchen Zhang  2 ,  Pu Chen  2 ,  Yao Luo  2 ,  Jia Gu  2 ,  Hongfeng Gu  2 ,  Ping Wei  4 ,  Yanan Sun  2 ,  Chunxiang Yin  2 ,  Hanxi Xing  2 ,  Yannan Luo  2 ,  Jing-Jing Zhang  2 ,  Qihua Zhu  2 ,  Yi Zou  2 ,  Yungen Xu  1  2
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Rice University, Houston, Texas 77005, United States.
  • 4. Hefei Institute of Pharmaceutical Industry Co. Ltd., Hefei 230601, China.
PMID: 41915886 DOI: 10.1021/acs.jmedchem.5c03457
Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that severely restricts patients' daily activities. TNF-α has become one of the important therapeutic targets for RA and Other autoimmune diseases. Herein, we report a series of small-molecule TNF-α inhibitors containing quinoline scaffold and spiro-ring structure. Among them, XS-18 was validated to have strong binding affinity for TNF-α (FP IC50 = 123 nM; KD = 45.9 nM). In addition, XS-18 exhibits significant inhibitory activity against TNF-α mediated inflammatory pathways in vitro. In collagen-induced arthritis (CIA) mouse model, oral administration of XS-18 demonstrated strong anti-inflammatory effects, and its efficacy in promoting joint cartilage repair was superior to that of tofacitinib. XS-18 also exhibiting better pharmacokinetic properties (T1/2 = 7.1 h, F = 56.8%). These findings indicate that XS-18, a small-molecule TNF-α inhibitor, has the potential to serve as an effective oral therapeutic agent for the treatment of autoimmune diseases.

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