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

Title
Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson's Disease Therapy
Authors
배애님이재익박기덕박종현김진우우서연최지원신수정한상문김현정김시원이창호한균희
Issue Date
2019-01
Publisher
Journal of medicinal chemistry
Citation
VOL 62, NO 2-830
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/68925
ISSN
0022-2623
Appears in Collections:
KIST Publication > Article
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE