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

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, <b>XS-18</b> was validated to have strong binding affinity for TNF-α (FP IC₅₀ = 123 nM; <i>K</i>_D = 45.9 nM). In addition, <b>XS-18</b> exhibits significant inhibitory activity against TNF-α mediated inflammatory pathways in vitro. In collagen-induced arthritis (CIA) mouse model, oral administration of <b>XS-18</b> demonstrated strong anti-inflammatory effects, and its efficacy in promoting joint cartilage repair was superior to that of tofacitinib. <b>XS-18</b> also exhibiting better pharmacokinetic properties (<i>T</i>_1/2 = 7.1 h, <i>F</i> = 56.8%). These findings indicate that <b>XS-18</b>, a small-molecule TNF-α inhibitor, has the potential to serve as an effective oral therapeutic agent for the treatment of autoimmune diseases.