4-((5-((1-(2,3-dihydroxypropyl)piperidin-4-yl)amino)isoindolin-2-yl)sulfonyl)benzene-1,3-diol

• 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: 4-((5-((1-(2,3-dihydroxypropyl)piperidin-4-yl)amino)isoindolin-2-yl)sulfonyl)benzene-1,3-diol
• 英文别名: 4-[[5-[[1-(2,3-Dihydroxypropyl)piperidin-4-yl]amino]-1,3-dihydroisoindol-2-yl]sulfonyl]benzene-1,3-diol；4-[[5-[[1-(2,3-dihydroxypropyl)piperidin-4-yl]amino]-1,3-dihydroisoindol-2-yl]sulfonyl]benzene-1,3-diol
• 化学式: C₂₂H₂₉N₃O₆S
• 分子量: 463.555
• InChiKey: DYIWTVOQUHVIHZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  142
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-溴邻苯二甲酰亚胺 在 盐酸 、 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 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 、 环己烯 为溶剂， 反应 231.5h， 生成 4-((5-((1-(2,3-dihydroxypropyl)piperidin-4-yl)amino)isoindolin-2-yl)sulfonyl)benzene-1,3-diol
  参考文献：
  名称：

  [EN] Dihydroxyphenyl Sulfonylisoindoline Derivatives
  [FR] DÉRIVÉS DE DIHYDROXYPHÉNYLE SULFONYLISOINDOLINE

  摘要：

  提供了抑制丙酮酸脱氢酶激酶（PDK）的化合物，以及其药用可接受的盐、氢化物和立体异构体。这些化合物用于制备药物组合物，以及制备和使用的方法，包括使用有效量的化合物或组合物治疗需要的人。

  公开号：

  WO2018095260A1

文献信息

• [EN] Dihydroxyphenyl Sulfonylisoindoline Derivatives<br/>[FR] DÉRIVÉS DE DIHYDROXYPHÉNYLE SULFONYLISOINDOLINE
  申请人：NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING

  公开号：WO2018095260A1

  公开（公告）日：2018-05-31

  Provided are compounds that are inhibitors of pyruvate dehydrogenase kinase (PDK), and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition.

  提供了抑制丙酮酸脱氢酶激酶（PDK）的化合物，以及其药用可接受的盐、氢化物和立体异构体。这些化合物用于制备药物组合物，以及制备和使用的方法，包括使用有效量的化合物或组合物治疗需要的人。
• Inhibitors of mitochondrial pyruvate dehydrogenase kinase isoforms 1-4 and uses thereof
  申请人：The Board of Regents of the University of Texas System

  公开号：US10167258B2

  公开（公告）日：2019-01-01

  The present disclosure relates to the identification of PDK inhibitors and their use in the treatment of diseases such as diabetes, cardiovascular disease and cancer. The invention relates to the development of robust PDK inhibitors that can be used to improve glucose metabolism and correct metabolic dysfunction in vivo. Based on the unique structural features present in the ATP-binding pocket of PDK2, a single functional-group change was made in a known Hsp90 inhibitor that binds to the corresponding pocket of the latter protein from the GHKL family. This approach efficiently converted the Hsp90 inhibitor to a highly specific inhibitor for all PDK isoforms. These final PDK inhibitors of this series robustly augments PDC activity with reduced phosphorylation in tissues.

  本公开涉及 PDK 抑制剂的鉴定及其在治疗糖尿病、心血管疾病和癌症等疾病中的应用。本发明涉及开发可用于改善葡萄糖代谢和纠正体内代谢功能障碍的强效 PDK 抑制剂。根据 PDK2 的 ATP 结合口袋中存在的独特结构特征，对已知的 Hsp90 抑制剂进行了单官能团改变，使其与 GHKL 家族后一种蛋白质的相应口袋结合。这种方法有效地将 Hsp90 抑制剂转变成了一种针对所有 PDK 同工酶的高度特异性抑制剂。该系列的最后几种 PDK 抑制剂可增强 PDC 的活性，同时降低组织中的磷酸化。
• INHIBITORS OF MITOCHONDRIAL PYRUVATE DEHYDROGENASE KINASE ISOFORMS 1-4 AND USES THEREOF
  申请人：THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

  公开号：US20170001958A1

  公开（公告）日：2017-01-05

  The present disclosure relates to the identification of PDK inhibitors and their use in the treatment of diseases such as diabetes, cardiovascular disease and cancer. The invention relates to the development of robust PDK inhibitors that can be used to improve glucose metabolism and correct metabolic dysfunction in vivo. Based on the unique structural features present in the ATP-binding pocket of PDK2, a single functional-group change was made in a known Hsp90 inhibitor that binds to the corresponding pocket of the latter protein from the GHKL family. This approach efficiently converted the Hsp90 inhibitor to a highly specific inhibitor for all PDK isoforms. These final PDK inhibitors of this series robustly augments PDC activity with reduced phosphorylation in tissues.
• [EN] INHIBITORS OF MITOCHNONDRIAL PYRUVATE DEHYDROGENASE KINASE ISOFORMS 1-4 AND USES THEREOF<br/>[FR] INHIBITEURS D'ISOFORMES DE PYRUVATE DÉSHYDROGÉNASE KINASE MITOCHONDRIALES 1-4 ET LEURS UTILISATIONS
  申请人：UNIV TEXAS

  公开号：WO2015089360A1

  公开（公告）日：2015-06-18

  The present disclosure relates to the identification of PDK inhibitors and their use in the treatment of diseases such as diabetes, cardiovascular disease and cancer. The invention relates to the development of robust PDK inhibitors that can be used to improve glucose metabolism and correct metabolic dysfunction in vivo. Based on the unique structural features present in the ATP-binding pocket of PDK2, a single functional-group change was made in a known Hsp90 inhibitor that binds to the corresponding pocket of the latter protein from the GHKL family. This approach efficiently converted the Hsp90 inhibitor to a highly specific inhibitor for all PDK isoforms. These final PDK inhibitors of this series robustly augments PDC activity with reduced phosphorylation in tissues.
• 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.