- Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson's Disease Therapy
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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.
- Choi, Ji Won,Kim, Siwon,Park, Jong-Hyun,Kim, Hyeon Jeong,Shin, Su Jeong,Kim, Jin Woo,Woo, Seo Yeon,Lee, Changho,Han, Sang Moon,Lee, Jaeick,Pae, Ae Nim,Han, Gyoonhee,Park, Ki Duk
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supporting information
p. 811 - 830
(2019/01/08)
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- Discovery of vinyl sulfones as a novel class of neuroprotective agents toward Parkinson's disease therapy
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Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. 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 antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.
- Woo, Seo Yeon,Kim, Ji Hyun,Moon, Mi Kyeong,Han, Se-Hee,Yeon, Seul Ki,Choi, Ji Won,Jang, Bo Ko,Song, Hyo Jung,Kang, Yong Gu,Kim, Jin Woo,Lee, Jaeick,Kim, Dong Jin,Hwang, Onyou,Park, Ki Duk
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supporting information
p. 1473 - 1487
(2014/03/21)
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