(E)-4-(3-(4-((2-(3′-fluoropyridin-2′-yl)vinyl)sulfonyl)phenoxy)propyl)morpholine hydrochloride

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (E)-4-(3-(4-((2-(3′-fluoropyridin-2′-yl)vinyl)sulfonyl)phenoxy)propyl)morpholine hydrochloride
• 英文别名: 4-[3-[4-[(E)-2-(3-fluoropyridin-2-yl)ethenyl]sulfonylphenoxy]propyl]morpholine;hydrochloride
• 化学式: C₂₀H₂₃FN₂O₄S*ClH
• 分子量: 442.939
• InChiKey: AGAQGTBXHZGAGE-OHGISNTKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.19
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  77.1
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-(3-羟丙基)吗啉 在 盐酸 、 正丁基锂 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 环己烷 、 乙酸乙酯 、 乙腈 为溶剂， 反应 5.5h， 生成 (E)-4-(3-(4-((2-(3′-fluoropyridin-2′-yl)vinyl)sulfonyl)phenoxy)propyl)morpholine hydrochloride
  参考文献：
  名称：

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

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.8b01527

文献信息

• NOVEL HALO-(3-(PHENYLSULFONYL)PROP-1-ENYL)PYRIDINE DERIVATIVE AND USE THEREOF
  申请人：Korea Institute of Science and Technology

  公开号：EP3838896A1

  公开（公告）日：2021-06-23

  The present invention relates to a novel halo-(3-(phenylsulfonyl)prop-1-enyl)pyridine derivative or a pharmaceutically acceptable salt thereof; a preparation method thereof; and an Nrf2 activator and a pharmaceutical composition for preventing or treating diseases induced by a decrease in Nrf2 activity, both of which comprise the same as an active ingredient.

  本发明涉及一种新型卤代-(3-(苯磺酰基)丙-1-烯基)吡啶衍生物或其药学上可接受的盐；其制备方法；以及一种 Nrf2 激活剂和一种用于预防或治疗因 Nrf2 活性降低而诱发的疾病的药物组合物，二者均包含相同的活性成分。
• EP3838896
  申请人：——

  公开号：——

  公开（公告）日：——
• Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson’s Disease Therapy
  作者：Ji Won Choi、Siwon Kim、Jong-Hyun Park、Hyeon Jeong Kim、Su Jeong Shin、Jin Woo Kim、Seo Yeon Woo、Changho Lee、Sang Moon Han、Jaeick Lee、Ae Nim Pae、Gyoonhee Han、Ki Duk Park

  DOI：10.1021/acs.jmedchem.8b01527

  日期：2019.1.24

  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.