Convergence Research Center for Diagnosis, Treatment & Care System of Dementia , Korea Institute of Science & Technology (KIST) , Seoul 02792 , Republic of Korea.
Division of Bio-Med Science & Technology, KIST School , Korea University of Science and Technology , Seoul 02792 , Republic of Korea.
J Med Chem. 2019 Jan 24;62(2):811-830. doi: 10.1021/acs.jmedchem.8b01527. Epub 2018 Dec 20.
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 (EC) = 346 nM; 1: EC = 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.
我们之前开发了一系列新型的乙烯砜类化合物，作为核因子红细胞 2 相关因子 2（Nrf2）激活剂，具有治疗帕金森病（PD）的潜力。然而，之前开发的先导化合物（1）表现出不理想的类药性。在这里，我们通过引入氮杂环来优化乙烯砜类化合物，以改善类药性。在所合成的化合物中，17e 是最有前途的候选药物，具有良好的类药性。与化合物 1 相比，化合物 17e 在基于细胞的测定中对 Nrf2 激活具有更好的效果（17e：半最大有效浓度（EC）= 346 nM；1：EC = 530 nM）。化合物 17e 进一步被证实能够诱导 Nrf2 依赖性抗氧化酶在 mRNA 和蛋白质水平上的表达。在 1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的 PD 小鼠模型中，17e 显著减轻了酪氨酸羟化酶免疫阳性多巴胺能神经元的丢失，抑制了小胶质细胞的激活，并缓解了与 PD 相关的运动功能障碍。因此，17e 是一种具有优异类药性的新型 Nrf2 激活剂，代表了 PD 的一种潜在治疗候选药物。
