Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2‑Related Factor 2 (Nrf2) Activators for Parkinson’s Disease Therapy

We previously developed a novel series
of vinyl sulfones as nuclear
factor erythroid 2-related factor 2 (Nrf2) activators with therapeutic
potential for Parkinson’s disease (PD). However, the previously
developed lead compound (1) exhibited undesirable druglike
properties. Here, we optimized vinyl sulfones by introducing nitrogen
heterocycles to improve druglike properties. Among the synthesized
compounds, 17e was the most promising drug candidate
with good druglike properties. Compound 17e showed superior
effects on Nrf2 activation in cell-based assays compared to compound 1 (17e: half-maximal effective concentration
(EC50) = 346 nM; 1: EC50 = 530
nM). Compound 17e was further confirmed to induce expression
of Nrf2-dependent antioxidant enzymes at both mRNA and protein levels.
In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model
of PD, 17e significantly attenuated loss of tyrosine
hydroxylase-immunopositive dopaminergic neurons, suppressed microglial
activation, and alleviated PD-associated motor dysfunction. Thus, 17e is a novel Nrf2 activator with excellent druglike properties
and represents a potential therapeutic candidate for PD.