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 (EC 50 ) = 346 nM; 1: EC 50 = 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.
Bibliographical noteFunding Information:
This study was supported by a National Research Council of Science & Technology grant by the South Korean government (MSIP, No. CRC-15-04-KIST), the National Research Foundation of Korea (NRF-2018M3A9C8016849), and Main Research Program (E0164503-01) of the Korea Food Research Institute.
© 2018 American Chemical Society.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery