6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(3-(hydroxymethyl)piperidin-1-yl)-4-(trifluoromethyl)nicotinonitrile

• 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: 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(3-(hydroxymethyl)piperidin-1-yl)-4-(trifluoromethyl)nicotinonitrile
• 英文别名: 6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-[3-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile；6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-[3-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile
• 化学式: C₁₉H₂₆F₃N₅O₂
• 分子量: 413.443
• InChiKey: XNJVLRJGPUMHDH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  86.9
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  3-氰基-2,6-二氯-4-(三氟甲基)吡啶 在 碳酸氢钠 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(3-(hydroxymethyl)piperidin-1-yl)-4-(trifluoromethyl)nicotinonitrile
  参考文献：
  名称：

  Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)

  摘要：

  Increased fructose consumption and its subsequent Metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective. KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.

  DOI：

  10.1021/acs.jmedchem.7b00947

文献信息

• COMPOSITIONS AND METHODS FOR TARGETING FRUCTOSE ENZYMES AND TRANSPORTERS FOR THE TREATMENT OF CANCER
  申请人：Duke University

  公开号：US20190231761A1

  公开（公告）日：2019-08-01

  The disclosure relates to compositions and methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a therapeutic agent capable of down-regulating and/or inhibiting a fructose enzyme or fructose transporter in a cell of the subject such that the cancer growth is suppressed.
• Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)
  作者：Kim Huard、Kay Ahn、Paul Amor、David A. Beebe、Kris A. Borzilleri、Boris A. Chrunyk、Steven B. Coffey、Yang Cong、Edward L. Conn、Jeffrey S. Culp、Matthew S. Dowling、Matthew F. Gorgoglione、Jemy A. Gutierrez、John D. Knafels、Erik A. Lachapelle、Jayvardhan Pandit、Kevin D. Parris、Sylvie Perez、Jeffrey A. Pfefferkorn、David A. Price、Brian Raymer、Trenton T. Ross、Andre Shavnya、Aaron C. Smith、Timothy A. Subashi、Gregory J. Tesz、Benjamin A. Thuma、Meihua Tu、John D. Weaver、Yan Weng、Jane M. Withka、Gang Xing、Thomas V. Magee

  DOI：10.1021/acs.jmedchem.7b00947

  日期：2017.9.28

  Increased fructose consumption and its subsequent Metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective. KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.