ethyl 2-[5-chloro-2-[[2-(2,4-difluorophenoxy)-2-methylpropanoyl]amino]thiazol-4-yl]acetate | 1052720-28-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 2-[5-chloro-2-[[2-(2,4-difluorophenoxy)-2-methylpropanoyl]amino]thiazol-4-yl]acetate
• 英文别名: {5-chloro-2-[2-(2,4-difluoro-phenoxy)-2-methyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester；Ethyl 2-[5-chloro-2-[[2-(2,4-difluorophenoxy)-2-methylpropanoyl]amino]-1,3-thiazol-4-yl]acetate
• CAS: 1052720-28-1
• 化学式: C₁₇H₁₇ClF₂N₂O₄S
• 分子量: 418.849
• InChiKey: MPZPQHDFSAZZDM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl 2-[5-chloro-2-[[2-(2,4-difluorophenoxy)-2-methylpropanoyl]amino]thiazol-4-yl]acetate 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 12.0h， 以67%的产率得到2-[5-chloro-2-[[2-(2,4-difluorophenoxy)-2-methylpropanoyl]amino]thiazol-4-yl]acetic 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-(2,4-二氟苯氧基)-2-甲基丙酸乙酯 在 N-甲基吗啉 、 lithium hydroxide monohydrate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 ethyl 2-[5-chloro-2-[[2-(2,4-difluorophenoxy)-2-methylpropanoyl]amino]thiazol-4-yl]acetate
  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

• 2,2,2-TRI-SUBSTITUTED ACETAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS, THEIR PROCESS AND PHARMACEUTICAL APPLICATION
  申请人：Mookhtiar Kasim A.

  公开号：US20100144772A1

  公开（公告）日：2010-06-10

  Compounds of the present disclosure are 2,2,2-tri-substituted acetamide derivatives of formula (I), its polymorphs, stereoisomers, prodrugs, solvates, pharmaceutically acceptable salts and formulations thereof, useful as Glucokinase activator. Processes of their preparation are also described in the disclosure. The disclosure also describes method to characterize partial glucokinase activators.

  本公开涉及的化合物是式(I)的2,2,2-三取代乙酰胺衍生物，其多晶形态、立体异构体、前药、溶剂化物、药学上可接受的盐和制剂，可用作葡萄糖激酶激活剂。公开还描述了它们的制备过程。公开还描述了表征部分葡萄糖激酶激活剂的方法。
• US8940900B2
  申请人：——

  公开号：US8940900B2

  公开（公告）日：2015-01-27
• [EN] 2,2,2-TRI-SUBSTITUTED ACETAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS, THEIR PROCESS AND PHARMACEUTICAL APPLICATION<br/>[FR] DÉRIVÉS D'ACÉTAMIDE 2,2,2-TRI-SUBSTITUÉ EN TANT QU'ACTIVATEURS DE LA GLUCOKINASE, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR APPLICATION PHARMACEUTIQUE
  申请人：ADVINUS THERAPEUTICS PRIVATE L

  公开号：WO2008104994A2

  公开（公告）日：2008-09-04

  [EN] Compounds of the present disclosure are 2,2,2-tri-substituted acetamide derivatives of formula (I), its polymorphs, stereoisomers, prodrugs, solvates, pharmaceutically acceptable salts and formulations thereof, useful as Glucokinase activator. Processes of their preparation are also described in the disclosure. The disclosure also describes method to characterize partial glucokinase activators.
  [FR] Les composés de la présente invention sont des dérivés d'acétamide 2,2,2-tri-substitué représentés par la formule (I), leurs polymorphes, stéréoisomères, promédicaments, solvates, des formulations et des sels pharmaceutiquement acceptables de ceux-ci, utiles en tant qu'activateur de la glucokinase. L'invention concerne également des procédés pour leur préparation. L'invention concerne en outre un procédé de caractérisation d'activateurs partiels de la glucokinase.
• 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.