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 drug-like properties. Here, we optimized vinyl sulfones by introducing nitrogen heterocycles to improve drug-like properties. Among the synthesized compounds, 17e was the most promising drug candidate with good drug-like properties. Compound 17e showed superior effects on Nrf2 activation in cell-based assays compared to compound 1 (17e: 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 (MPTP)-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 drug-like properties and represents a potential therapeutic candidate for PD.