Discovery and Optimization of a Series of Vinyl Sulfoximine-Based Analogues as Potent Nrf2 Activators for the Treatment of Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated neurodegenerative
disease of the central nervous system (CNS), which leads to demyelination,
axonal loss, and neurodegeneration. Increased oxidative stress and
neurodegeneration have been implicated in all stages of MS, making
neuroprotective therapeutics a promising strategy for its treatment.
We previously have reported vinyl sulfones with antioxidative and
anti-inflammatory properties that activate nuclear factor erythroid
2-related factor 2 (Nrf2), a transcription factor that induces the
expression of cytoprotective genes against oxidative stress. In this
study, we synthesized vinyl sulfoximine derivatives by modifying the
core structure and determined therapeutic potential as Nrf2 activators.
Among them, 10v effectively activated Nrf2 (EC50 = 83.5 nM) and exhibited favorable drug-like properties. 10v successfully induced expression of Nrf2-dependent antioxidant enzymes
and suppressed lipopolysaccharide (LPS)-induced inflammatory responses
in BV-2 microglial cells. We also confirmed that 10v effectively
reversed disease progression and attenuated demyelination in an experimental
autoimmune encephalitis (EAE) mouse model of MS.