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, 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.