4-((5-(piperazin-1-yl)isoindolin-2-yl)sulfonyl)benzene-1,3-diol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-((5-(piperazin-1-yl)isoindolin-2-yl)sulfonyl)benzene-1,3-diol
• 英文别名: 4-[(5-Piperazin-1-yl-1,3-dihydroisoindol-2-yl)sulfonyl]benzene-1,3-diol；4-[(5-piperazin-1-yl-1,3-dihydroisoindol-2-yl)sulfonyl]benzene-1,3-diol
• 化学式: C₁₈H₂₁N₃O₄S
• 分子量: 375.448
• InChiKey: NTMRCMKXVDLSFA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-溴邻苯二甲酰亚胺 在 tris-(dibenzylideneacetone)dipalladium(0) 、 palladium on activated charcoal 、 三氟化硼 、 氢气 、 三溴化硼 、 potassium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 、 环己烯 为溶剂， 反应 159.5h， 生成 4-((5-(piperazin-1-yl)isoindolin-2-yl)sulfonyl)benzene-1,3-diol
  参考文献：
  名称：

  Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors

  摘要：

  Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide (17) shows a similar to 8-fold lower IC50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.

  DOI：

  10.1021/acs.jmedchem.6b01540

文献信息

• Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors
  作者：Shih-Chia Tso、Mingliang Lou、Cheng-Yang Wu、Wen-Jun Gui、Jacinta L. Chuang、Lorraine K. Morlock、Noelle S. Williams、R. Max Wynn、Xiangbing Qi、David T. Chuang

  DOI：10.1021/acs.jmedchem.6b01540

  日期：2017.2.9

  Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide (17) shows a similar to 8-fold lower IC50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.