122nd General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Grand Ballroom
Time 10월 18일 (목요일) 11:00~12:30
Code MEDI.P-319
Subject Optimization of Vinyl Sulfone Derivatives as Potent Nrf2 Activator for Parkinson’s Disease Therapy
Authors Ji Won Choi, Siwon Kim, Jong-Hyun Park, Hyeon Jeong Kim, Su Jeong Shin, Ki Duk Park*
Convergence Research Center for DTC of Dementia, Korea Institute of Science and Technology, Korea
Abstract We previously developed a novel series of vinyl sulfones as Nrf2 activators with a therapeutic potential for Parkinson’s disease (PD). However, the previously developed lead compound (1) exhibited undesirable drug-like properties such as solubility, metabolic stability, CYP inhibition and hERG safety. Here, we have optimized a class of vinyl sulfones introducing pyridine and morpholine moieties to improve drug-like properties. Among the synthesized compounds, 17e is the most promising drug candidate with excellent drug-like properties such as good solubility, high human microsomal/plasma stability, low CYP inhibition and excellent hERG safety. In addition, 17e showed superior effect on Nrf2 activation in the cell based assay compared to compound 1 (17e; EC50:346 nM vs 1; EC50:530 nM). 17e was further confirmed to induce expression of the Nrf2-dependent anti-oxidant enzymes NQO1, GCLC, GCLM, and HO-1, at both mRNA and protein levels. In the MPTP-induced mouse model of PD, 17e significantly attenuated the loss of tyrosine hydroxylase (TH)-immunopositive dopaminergic neurons, suppressed microglial activation, and alleviated the PD-associated motor dysfunction. In conclusion, we present 17e as a novel Nrf2 activator with excellent drug-like properties and potential therapeutic candidate for PD.
E-mail jiwon0602@kist.re.kr