123rd General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2
Time 4월 18일 (목요일) 11:00~12:30
Code MEDI.P-397
Subject Development and Optimization of Halogenated Vinyl Sulfones as Nrf2 Activators for the Treatment of Parkinson’s Disease
Authors Jong Seok Yoo, Ki Duk Park*
Convergence Research Center for Dementia, Korea Institute of Science and Technology, Korea
Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder which is characterized by abnormalities in motor control and muscle rigidity. Recent studies suggest that oxidative stress causes the striatal dopamine (DA) deficiency by neuronal loss in the substantia nigra (SN). The Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of various antioxidant enzyme genes. In previous work, we have synthesized novel vinyl sulfone derivatives as Nrf2 activator. The lead compound KDS4048 was confirmed to activate Nrf2 and to induce expression of the Nrf2 dependent antioxidant enzymes such as NQO1, GCLC, GLCM, and HO-1 at both mRNA and protein levels in dopaminergic neuronal cells. In this work, we have optimized the lead compound KDS4048 (EC50=530 nM) to improve drug-like properties and increase potency of Nrf2 activation. Compounds were synthesized by introducing halogen groups and pyridine ring into the vinyl sulfones. Among the synthesized compounds, KDS7001 and KDS7011 exhibited potent effect on Nrf2 activation (KDS7001 EC50=217 nM, KDS7011 EC50=213 nM) in cell-based assay. We will further evaluate whether two compounds induce the expression of anti-oxidant response genes NQO1, GCLC, GLCM, and HO-1 at both mRNA and protein levels and attenuate the PD-like motor dysfunctions in the MPTP-induced mice model of PD.
E-mail t18074@kist.re.kr