Discovery and\nOptimization of a Series of Vinyl Sulfoximine-Based\nAnalogues as Potent Nrf2 Activators for the Treatment of Multiple\nSclerosis

Multiple sclerosis (MS) is an immune-mediated neurodegenerative\ndisease of the central nervous system (CNS), which leads to demyelination,\naxonal loss, and neurodegeneration. Increased oxidative stress and\nneurodegeneration have been implicated in all stages of MS, making\nneuroprotective therapeutics a promising strategy for its treatment.\nWe previously have reported vinyl sulfones with antioxidative and\nanti-inflammatory properties that activate nuclear factor erythroid\n2-related factor 2 (Nrf2), a transcription factor that induces the\nexpression of cytoprotective genes against oxidative stress. In this\nstudy, we synthesized vinyl sulfoximine derivatives by modifying the\ncore structure and determined therapeutic potential as Nrf2 activators.\nAmong them, <b>10v</b> effectively activated Nrf2 (EC<sub>50</sub> = 83.5 nM) and exhibited favorable drug-like properties. <b>10v</b> successfully induced expression of Nrf2-dependent antioxidant enzymes\nand suppressed lipopolysaccharide (LPS)-induced inflammatory responses\nin BV-2 microglial cells. We also confirmed that <b>10v</b> effectively\nreversed disease progression and attenuated demyelination in an experimental\nautoimmune encephalitis (EAE) mouse model of MS.