methyl 4-[2-[[2-(2,4-difluorophenoxy)-2-(4-pyrrolidin-1-ylsulfonylphenyl)acetyl]amino]thiazol-5-yl]oxybenzoate | 1328991-70-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: methyl 4-[2-[[2-(2,4-difluorophenoxy)-2-(4-pyrrolidin-1-ylsulfonylphenyl)acetyl]amino]thiazol-5-yl]oxybenzoate
• 英文别名: 4-(2-{2-(2,4-difluoro-phenoxy)-2-[4-(pyrrolidine-1-sulfonyl)-phenyl]-acetylamino}-thiazol-5-yloxy)-benzoic acid methyl ester；Methyl 4-[[2-[[2-(2,4-difluorophenoxy)-2-(4-pyrrolidin-1-ylsulfonylphenyl)acetyl]amino]-1,3-thiazol-5-yl]oxy]benzoate；methyl 4-[[2-[[2-(2,4-difluorophenoxy)-2-(4-pyrrolidin-1-ylsulfonylphenyl)acetyl]amino]-1,3-thiazol-5-yl]oxy]benzoate
• CAS: 1328991-70-3
• 化学式: C₂₉H₂₅F₂N₃O₇S₂
• 分子量: 629.662
• InChiKey: JXWATQRYEMDZMJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  43
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  161
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methyl 4-[2-[[2-(2,4-difluorophenoxy)-2-(4-pyrrolidin-1-ylsulfonylphenyl)acetyl]amino]thiazol-5-yl]oxybenzoate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 18.0h， 生成 4-[2-[[2-(2,4-difluorophenoxy)-2-(4-pyrrolidin-1-ylsulfonylphenyl)acetyl]amino]thiazol-5-yl]oxybenzoic acid
  参考文献：
  名称：

  Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia

  摘要：

  Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.03.042
• 作为产物：
  描述：

  4-巯基苯基乙酸 在 N-溴代丁二酰亚胺(NBS) 、 三甲基氯硅烷 、 2,4-二氟苯酚 、 硫酸 、 1-羟基苯并三唑 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 potassium nitrate 、 lithium hydroxide 、 过氧化苯甲酰 作用下， 以 四氢呋喃 、 甲醇 、 四氯化碳 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 111.5h， 生成 methyl 4-[2-[[2-(2,4-difluorophenoxy)-2-(4-pyrrolidin-1-ylsulfonylphenyl)acetyl]amino]thiazol-5-yl]oxybenzoate
  参考文献：
  名称：

  Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia

  摘要：

  Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.03.042

文献信息

• ACETAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS, THEIR PROCESS AND MEDICINAL APPLICATION
  申请人：Bhuniya Debnath

  公开号：US20100310493A1

  公开（公告）日：2010-12-09

  Acetamide derivatives, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, are disclosed. The disclosure also provides process of preparation of these acetamide derivatives.

  乙酰胺衍生物，它们的立体异构体、互变异构体、前药、药用可接受盐、多型体、溶剂合物及其配方，用于预防、管理、治疗、控制疾病和/或医疗状况的进展，或者作为激活葡萄糖激酶有益时的辅助治疗，已被披露。该披露还提供了这些乙酰胺衍生物的制备方法。
• Acetamide compounds as glucokinase activators, their process and medicinal applications
  申请人：Impetis Biosciences Ltd.

  公开号：EP2402327B1

  公开（公告）日：2018-03-07
• US8501955B2
  申请人：——

  公开号：US8501955B2

  公开（公告）日：2013-08-06
• Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia
  作者：Anil M. Deshpande、Debnath Bhuniya、Siddhartha De、Bhavesh Dave、Vinod P. Vyavahare、Santosh H. Kurhade、Sachin R. Kandalkar、Keshav P. Naik、Balasaheb S. Kobal、Rahul D. Kaduskar、Sujay Basu、Vaibhav Jain、Pratima Patil、Sandhya Chaturvedi Joshi、Ganesh Bhat、Amol A. Raje、Satyanarayana Reddy、Jayasagar Gundu、Vamsi Madgula、Suhas Tambe、Prasad Shitole、Dhananjay Umrani、Anita Chugh、Venkata P. Palle、Kasim A. Mookhtiar

  DOI：10.1016/j.ejmech.2017.03.042

  日期：2017.6

  Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia. (C) 2017 Elsevier Masson SAS. All rights reserved.