Neuromyelitis optica (NMO) is a demyelinating autoimmune disease of the optic nerve and spinal cord triggered by binding of NMO-specific immunoglobulin G (NMO-IgG) auto-antibodies to the water channel aquaporin-4 (AQP4) in astrocytes. To find potential NMO therapeutics, a screening system was established and used to identify inhibitors of NMO-IgG-mediated complement-dependent cytotoxicity (CDC). The screening of approximately 400 compounds yielded potent hit compounds with inhibitory effects against CDC in U87-MG cells expressing human AQP4. Derivatives of the hit compounds were synthesized and evaluated for their inhibition of CDC. Of the small molecules synthesized, (E)-1-(2-((4-methoxyphenyl)sulfonyl)vinyl)-[4-[(3-trifluoromethyl)phenyl] methoxy]benzene (5 c) showed the most potent activity in both stably transfected U87-MG cells and mice-derived astrocytes. The results of this study suggest that 5 c, which targets NMO-IgG-specific CDC, may be useful as a research tool and a potential candidate for therapeutic development for the treatment of NMO.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry