methyl 3-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)acetyl]amino]thiazol-5-yl]oxybenzoate | 1328984-60-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: methyl 3-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)acetyl]amino]thiazol-5-yl]oxybenzoate
• 英文别名: 3-{2-[2-(4-cyclopropane-sulfonyl-phenyl)-2-(2,4-difluoro-phenoxy)acetyl-amino]thiazol-5-yloxy}benzoic acid methyl ester；Methyl 3-[[2-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)acetyl]amino]-1,3-thiazol-5-yl]oxy]benzoate
• CAS: 1328984-60-6；1328992-30-8；1328992-31-9
• 化学式: C₂₈H₂₂F₂N₂O₇S₂
• 分子量: 600.621
• InChiKey: WZOLXXMSRHEIIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  158
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  methyl 3-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)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 3.0h， 生成 3-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)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：

  2-(4-环丙基硫烷基苯基)乙酸 在 N-溴代丁二酰亚胺(NBS) 、 氯化亚砜 、 potassium carbonate 、 三乙胺 、 间氯过氧苯甲酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 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 29.5h， 生成 methyl 3-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)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 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