ethyl 4-(3,5-dichlorophenylthio)-3-oxobutanoate | 1263406-26-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl 4-(3,5-dichlorophenylthio)-3-oxobutanoate
• 英文别名: Ethyl 4-(3,5-dichlorophenyl)sulfanyl-3-oxobutanoate；ethyl 4-(3,5-dichlorophenyl)sulfanyl-3-oxobutanoate
• CAS: 1263406-26-3
• 化学式: C₁₂H₁₂Cl₂O₃S
• 分子量: 307.197
• InChiKey: GLFUOXGZNMYHFZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  18
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  68.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 4-(3,5-dichlorophenylthio)-3-oxobutanoate 在 ammonium acetate 、 溶剂黄146 、 zinc(II) iodide 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 6.0h， 生成 ethyl 2-((3,5-dichlorophenylthio)methyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate
  参考文献：
  名称：

  Exploring the role of chloro and methyl substitutions in 2-phenylthiomethyl-benzoindole derivatives for 5-LOX enzyme inhibition

  摘要：

  Following the results we previously reported on a series of ethyl 2-phenylthiomethyl 5-hydroxyindole-3-carboxylate derivatives as 5-lipoxygenase (5-LOX) inhibitors, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand.The first level of structural modification involved the annelation of benzene to the indole, yielding corresponding benzo[g]indole derivatives, systematic optimization of methyl or chlorine groups in meta, ortho- and ortho/para-position of 2-phenylthiomethyl moiety were applied. The reported results show that extension of the aromatic core led to a great enhancement of activity, especially in cell-free assay, and the accurate structure-based design provided compounds 6f, 6g and 61 that block 5-LOX activity in cell-free assays with IC50 ranging from 0.17 to 0.22 mu M, and suppress 5-LOX product synthesis in polymorphonuclear leukocytes with IC50 ranging from 0.19 to 0.37 mu M. Moreover we have identified 6f and 61 as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase-1 (mPGES-1) inhibitors and compound 61 significantly reduces inflammatory reactions in the carrageenan-induced mouse paw oedema. The reported in vivo analysis, together with the accessible synthetic procedure, stimulate for the generation of further potent antinflammatory benzoindoles-based agents. (C) 2015 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2015.11.048
• 作为产物：
  描述：

  4-氯乙酰乙酸乙酯 、 3,5-二氯苯硫酚 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以62%的产率得到ethyl 4-(3,5-dichlorophenylthio)-3-oxobutanoate
  参考文献：
  名称：

  Exploring the role of chloro and methyl substitutions in 2-phenylthiomethyl-benzoindole derivatives for 5-LOX enzyme inhibition

  摘要：

  Following the results we previously reported on a series of ethyl 2-phenylthiomethyl 5-hydroxyindole-3-carboxylate derivatives as 5-lipoxygenase (5-LOX) inhibitors, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand.The first level of structural modification involved the annelation of benzene to the indole, yielding corresponding benzo[g]indole derivatives, systematic optimization of methyl or chlorine groups in meta, ortho- and ortho/para-position of 2-phenylthiomethyl moiety were applied. The reported results show that extension of the aromatic core led to a great enhancement of activity, especially in cell-free assay, and the accurate structure-based design provided compounds 6f, 6g and 61 that block 5-LOX activity in cell-free assays with IC50 ranging from 0.17 to 0.22 mu M, and suppress 5-LOX product synthesis in polymorphonuclear leukocytes with IC50 ranging from 0.19 to 0.37 mu M. Moreover we have identified 6f and 61 as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase-1 (mPGES-1) inhibitors and compound 61 significantly reduces inflammatory reactions in the carrageenan-induced mouse paw oedema. The reported in vivo analysis, together with the accessible synthetic procedure, stimulate for the generation of further potent antinflammatory benzoindoles-based agents. (C) 2015 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2015.11.048

文献信息

• ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis
  作者：Tian Chen、Radhia Benmohamed、Jinho Kim、Karen Smith、Daniel Amante、Richard I. Morimoto、Donald R. Kirsch、Robert J. Ferrante、Richard B. Silverman

  DOI：10.1021/jm2014277

  日期：2012.1.12

  Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure: The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD 1) induced toxicity and aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic lead for the treatment of this neurodegenerative disorder.
• Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis
  作者：Tian Chen、Radhia Benmohamed、Anthony C. Arvanites、Hantamalala Ralay Ranaivo、Richard I. Morimoto、Robert J. Ferrante、D. Martin Watterson、Donald R. Kirsch、Richard B. Silverman

  DOI：10.1016/j.bmc.2010.10.052

  日期：2011.1

  Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase 1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (1 and 2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (19) with an EC50 of 170 nM. To determine the suitability of this class of compounds for further optimization, 1 was subjected to a battery of pharmacokinetic assays; most of the properties of 1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound 2 was found to be blood-brain barrier penetrating with a brain/plasma ratio = 0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients. (C) 2010 Elsevier Ltd. All rights reserved.