methyl 4-[2-[[2-(2,4-difluorophenoxy)-2-[4-(1-piperidylsulfonyl)phenyl]acetyl]amino]thiazol-5-yl]oxybenzoate | 1328992-13-7

• 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-(1-piperidylsulfonyl)phenyl]acetyl]amino]thiazol-5-yl]oxybenzoate
• 英文别名: 4-(2-{2-(2,4-difluoro-phenoxy)-2-[4-(piperidine-1-sulfonyl)-phenyl]-acetylamino}-thiazol-5-yloxy)-benzoic acid methyl ester；Methyl 4-[[2-[[2-(2,4-difluorophenoxy)-2-(4-piperidin-1-ylsulfonylphenyl)acetyl]amino]-1,3-thiazol-5-yl]oxy]benzoate；methyl 4-[[2-[[2-(2,4-difluorophenoxy)-2-(4-piperidin-1-ylsulfonylphenyl)acetyl]amino]-1,3-thiazol-5-yl]oxy]benzoate
• CAS: 1328992-13-7
• 化学式: C₃₀H₂₇F₂N₃O₇S₂
• 分子量: 643.689
• InChiKey: GZKTVPTUBHBIAM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 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-(1-piperidylsulfonyl)phenyl]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-(1-piperidylsulfonyl)phenyl]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-甲基吗啉 、 N-溴代丁二酰亚胺(NBS) 、 三甲基氯硅烷 、 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-(1-piperidylsulfonyl)phenyl]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