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

• Published in: Journal of medicinal chemistry Vol. 62; no. 2; pp. 811 - 830
• Main Authors: Choi, Ji Won, Kim, Siwon, Park, Jong-Hyun, Kim, Hyeon Jeong, Shin, Su Jeong, Kim, Jin Woo, Woo, Seo Yeon, Lee, Changho, Han, Sang Moon, Lee, Jaeick, Pae, Ae Nim, Han, Gyoonhee, Park, Ki Duk
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24-01-2019
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01527

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.