N-(5-fluorothiazol-2-yl)-2-methyl-5-(1-(methylglycyl)pyrrolidin-2-yl)thiophene-3-carboxamide | 1259398-14-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(5-fluorothiazol-2-yl)-2-methyl-5-(1-(methylglycyl)pyrrolidin-2-yl)thiophene-3-carboxamide
• 英文别名: (-)-2-Methyl-5-[1-(2-methylaminoacetyl)pyrrolidin-2-yl]thiophene-3-carboxylic acid (5-fluorothiazol-2-yl)amide；2-Methyl-5-[1-(2-methylaminoacetyl)pyrrolidin-2-yl]thiophene-3-carboxylic acid (5-fluorothiazol-2-yl)amide；N-(5-fluoro-1,3-thiazol-2-yl)-2-methyl-5-[1-[2-(methylamino)acetyl]pyrrolidin-2-yl]thiophene-3-carboxamide
• CAS: 1259398-14-5
• 化学式: C₁₆H₁₉FN₄O₂S₂
• 分子量: 382.483
• InChiKey: AMFIMDSXQLJALM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(5-fluorothiazol-2-yl)-2-methyl-5-(1-(methylglycyl)pyrrolidin-2-yl)thiophene-3-carboxamide 在 盐酸 、 苄基三甲基氢氧化铵 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 3-((2-(2-(4-((5-fluorothiazol-2-yl)carbamoyl)-5-methylthiophen-2-yl)pyrrolidin-1-yl)-2-oxoethyl) (methyl)amino)propanoic acid hydrochloride
  参考文献：
  名称：

  Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus

  摘要：

  Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.06.060
• 作为产物：
  描述：

  tert-butyl (2-(2-(4-((5-fluorothiazol-2-yl)carbamoyl)-5-methylthiophen-2-yl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)carbamate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以99%的产率得到N-(5-fluorothiazol-2-yl)-2-methyl-5-(1-(methylglycyl)pyrrolidin-2-yl)thiophene-3-carboxamide
  参考文献：
  名称：

  Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus

  摘要：

  Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.06.060

文献信息

• NOVEL THIOPHENECARBOXAMIDE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
  申请人：Yamashita Tokuyuki

  公开号：US20120101137A1

  公开（公告）日：2012-04-26

  The object of the present invention is to provide a compound having a glucokinase-activating effect. A pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient: wherein X means a nitrogen atom or CR 6 , wherein R 6 means a hydrogen atom or a halogen atom; R 1 means a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylthio group; R 2 means a hydrogen atom or a fluorine atom; R 3 means a hydrogen atom or a C1-C6 alkyl group; and one of R 4 and R 5 means a hydrogen atom or a C1-C6 alkyl group, and the other means a C1-C6 alkylenecarboxylic acid, a C1-C6 alkylsulfonyl group, a C1-C6 alkylcarbonyl group, or CONH 2 .

  本发明的目的是提供一种具有激活葡萄糖激酶作用的化合物。一种包含以下通式（I）所表示的化合物或其药学上可接受的盐为活性成分的药物组合物：其中X代表一个氮原子或CR6，其中R6代表氢原子或卤素原子；R1代表氢原子、C1-C6烷基、C1-C6烷氧基或C1-C6烷硫基；R2代表氢原子或氟原子；R3代表氢原子或C1-C6烷基；而R4和R5中的一个代表氢原子或C1-C6烷基，另一个代表C1-C6烷基羧酸、C1-C6烷基磺酰基、C1-C6烷基羰基或CONH2。
• Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus
  作者：Hiroki Fujieda、Masakazu Kogami、Masao Sakairi、Noriyasu Kato、Mitsuhiro Makino、Naoki Takahashi、Toshiyuki Miyazawa、Satoko Harada、Tokuyuki Yamashita

  DOI：10.1016/j.ejmech.2018.06.060

  日期：2018.8

  Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy. (C) 2018 Elsevier Masson SAS. All rights reserved.