3-Isopropoxy-5-(2-(3-thienyl)ethoxy)benzoic acid

• 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: 3-Isopropoxy-5-(2-(3-thienyl)ethoxy)benzoic acid
• 英文别名: 3-isopropoxy-5-(2-thiophene-3-yl-ethoxy)-benzoyl chloride；3-Propan-2-yloxy-5-(2-thiophen-3-ylethoxy)benzoyl chloride
• 化学式: C₁₆H₁₇ClO₃S
• 分子量: 324.828
• InChiKey: MNKAAAYHFVKHOV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  21
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  63.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-Isopropoxy-5-(2-(3-thienyl)ethoxy)benzoic acid 在 吡啶 、 potassium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 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：

  3-(2-溴乙基)噻吩 在 草酰氯 、 potassium carbonate 、 N,N-二甲基甲酰胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 0.75h， 生成 3-Isopropoxy-5-(2-(3-thienyl)ethoxy)benzoic acid
  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

• [EN] N- ( PYRAZOLE- 3 -YL) -BENZAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS<br/>[FR] DÉRIVÉS DE N-(PYRAZOL-3-YL)-BENZAMIDE COMME ACTIVATEURS DE GLUCOKINASE
  申请人：MERCK PATENT GMBH

  公开号：WO2009046802A1

  公开（公告）日：2009-04-16

  Novel heterocyclic compounds of the formula (I) in which R1, R2, R3, R4, R5, R6, R7, Alk and D have the meanings indicate in Claim 1, are activators of glucokinase and can be used for the prevention and/or treatment of Diabetes Typ 1 and 2, obesity, neuropathy and/or nephropathy.

  化学式（I）中的新型杂环化合物，其中R1、R2、R3、R4、R5、R6、R7、Alk和D的含义如权利要求书中所示，是葡萄糖激酶的激活剂，可用于预防和/或治疗糖尿病1型和2型、肥胖症、神经病和/或肾病。
• NOVEL ACTIVATORS OF GLUCOKINASE
  申请人：Tian Feng

  公开号：US20110294758A1

  公开（公告）日：2011-12-01

  The present invention provides for novel compounds of Formulas I and II and pharmaceutically acceptable salts and co-crystals thereof which have glucokinsae activator activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucokinase activator is indicated, including Type 1 and 2 diabetes, impaired glucose tolerance, insulin resistance and hyperglycemia. The present invention also provides for processes of making the compounds of Formulas I and II, including salts and co-crystals thereof, and pharmaceutical compositions comprising the same.

  本发明提供了I和II式的新型化合物，以及其药学上可接受的盐和共晶体，具有葡萄糖激酶激活剂活性。本发明还提供了包括该化合物的制药组合物，以及治疗、预防、延迟发病时间或减少一种或多种葡萄糖激酶激活剂所指示的疾病或症状发展或进展的方法，包括1型和2型糖尿病、糖耐量受损、胰岛素抵抗和高血糖。本发明还提供了制备I和II式化合物（包括其盐和共晶体）以及包括该化合物的制药组合物的方法。
• Activators of glucokinase
  申请人：Metabasis Therapeutics, Inc.

  公开号：US10174062B2

  公开（公告）日：2019-01-08

  The present invention provides for novel compounds of Formulas I and II and pharmaceutically acceptable salts and co-crystals thereof which have glucokinsae activator activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucokinase activator is indicated, including Type 1 and 2 diabetes, impaired glucose tolerance, insulin resistance and hyperglycemia. The present invention also provides for processes of making the compounds of Formulas I and II, including salts and co-crystals thereof, and pharmaceutical compositions comprising the same.

  本发明提供了具有葡萄糖激酶激活剂活性的式 I 和式 II 的新型化合物及其药学上可接受的盐和共晶体。本发明进一步提供了包含上述化合物的药物组合物，以及治疗、预防、延缓发病时间或降低一种或多种葡萄糖激酶激活剂适用的疾病或病症（包括 1 型和 2 型糖尿病、糖耐量受损、胰岛素抵抗和高血糖症）的发生或发展风险的方法。本发明还提供了制造式 I 和式 II 化合物（包括其盐和共晶体）的工艺，以及包含这些化合物的药物组合物。
• 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.
• US8940927B2
  申请人：——

  公开号：US8940927B2

  公开（公告）日：2015-01-27