methyl 6-(3-isopropoxy-5-(2-(3-thienyl)ethoxy)benzamido)nicotinate | 852520-62-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: methyl 6-(3-isopropoxy-5-(2-(3-thienyl)ethoxy)benzamido)nicotinate
• CAS: 852520-62-8
• 化学式: C₂₃H₂₄N₂O₅S
• 分子量: 440.52
• InChiKey: OAPDQAAHCNMUQX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.59
• 重原子数：
  31.0
• 可旋转键数：
  9.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  86.75
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  methyl 6-(3-isopropoxy-5-(2-(3-thienyl)ethoxy)benzamido)nicotinate 在 potassium hydroxide 作用下， 以 四氢呋喃 为溶剂， 以74%的产率得到GKA 22
  参考文献：
  名称：

  Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose

  摘要：

  Synthetic allosteric activators of human glucokinase are receiving considerable attention as potential diabetes therapeutic agents. Although their mechanism of action is not fully understood, structural studies suggest that activator association requires prior formation of a binary enzyme glucose complex. Here, we demonstrate that three previously described activators associate with glucokinase in a glucose-independent fashion. Transient-state kinetic assays reveal a lag in enzyme progress curves that is systematically reduced when the enzyme is preincubated with activators. Isothermal titration calorimetry demonstrates that activator binding is enthalpically driven for all three compounds, whereas the entropic changes accompanying activator binding can be favorable or unfavorable. Viscosity variation experiments indicate that the k(cat) value of glucokinase is almost fully limited by product release, both in the presence and absence of activators, suggesting that activators impact a step preceding product release. The observation of glucose-independent allosteric activation of glucokinase has important implications for the refinement of future diabetes therapeutics and for the mechanism of kinetic cooperativity of mammalian glucokinase.

  DOI：

  10.1021/ml400061x
• 作为产物：
  描述：

  噻吩-3-乙醇 在 吡啶 、 草酰氯 、 溴 、 potassium carbonate 、 N,N-二甲基甲酰胺 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 2.75h， 生成 methyl 6-(3-isopropoxy-5-(2-(3-thienyl)ethoxy)benzamido)nicotinate
  参考文献：
  名称：

  Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose

  摘要：

  Synthetic allosteric activators of human glucokinase are receiving considerable attention as potential diabetes therapeutic agents. Although their mechanism of action is not fully understood, structural studies suggest that activator association requires prior formation of a binary enzyme glucose complex. Here, we demonstrate that three previously described activators associate with glucokinase in a glucose-independent fashion. Transient-state kinetic assays reveal a lag in enzyme progress curves that is systematically reduced when the enzyme is preincubated with activators. Isothermal titration calorimetry demonstrates that activator binding is enthalpically driven for all three compounds, whereas the entropic changes accompanying activator binding can be favorable or unfavorable. Viscosity variation experiments indicate that the k(cat) value of glucokinase is almost fully limited by product release, both in the presence and absence of activators, suggesting that activators impact a step preceding product release. The observation of glucose-independent allosteric activation of glucokinase has important implications for the refinement of future diabetes therapeutics and for the mechanism of kinetic cooperativity of mammalian glucokinase.

  DOI：

  10.1021/ml400061x

文献信息

• Discovery, synthesis and biological evaluation of novel glucokinase activators
  作者：Darren McKerrecher、Joanne V. Allen、Suzanne S. Bowker、Scott Boyd、Peter W.R. Caulkett、Gordon S. Currie、Christopher D. Davies、Mark L. Fenwick、Harold Gaskin、Emma Grange、Rod B. Hargreaves、Barry R. Hayter、Roger James、Keith M. Johnson、Craig Johnstone、Clifford D. Jones、Sarah Lackie、John W. Rayner、Rolf P. Walker

  DOI：10.1016/j.bmcl.2005.01.087

  日期：2005.4

  The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented. (c) 2005 Elsevier Ltd. All rights reserved.