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

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

  • J Med Chem. 2019 Jan 24;62(2):811-830. doi: 10.1021/acs.jmedchem.8b01527.
Ji Won Choi 1,  Siwon Kim 1 2,  Jong-Hyun Park 1,  Hyeon Jeong Kim 1 3,  Su Jeong Shin 1,  Jin Woo Kim 1,  Seo Yeon Woo 1,  Changho Lee 4,  Sang Moon Han 5,  Jaeick Lee 5,  Ae Nim Pae 1 2 6,  Gyoonhee Han 3,  Ki Duk Park 1 2 6
Affiliations

Affiliations

  • 1 Convergence Research Center for Diagnosis, Treatment & Care System of Dementia , Korea Institute of Science & Technology (KIST) , Seoul 02792 , Republic of Korea.
  • 2 Division of Bio-Med Science & Technology, KIST School , Korea University of Science and Technology , Seoul 02792 , Republic of Korea.
  • 3 Department of Biotechnology , Yonsei University , Seoul 03722 , Republic of Korea.
  • 4 Division of Functional Food Research , Korea Food Research Institute , Wanju-gun , Jeollabuk-do 55365 , Republic of Korea.
  • 5 Doping Control Center , KIST , Seoul 02792 , Republic of Korea.
  • 6 KHU-KIST Department of Converging Science and Technology , Kyung Hee University , Seoul 02447 , Republic of Korea.
PMID: 30540174 DOI: 10.1021/acs.jmedchem.8b01527
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.

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