1-methyl-5-(2-((6-(methylsulfonyl)pyridin-3-yl)oxy)-5-nitrophenyl)pyrrolidin-2-one | 1616280-63-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 1-methyl-5-(2-((6-(methylsulfonyl)pyridin-3-yl)oxy)-5-nitrophenyl)pyrrolidin-2-one
• 英文别名: 1-Methyl-5-[2-[[6-(methylsulfonyl)-3-pyridinyl]oxy]-5-nitrophenyl]-2-pyrrolidinone；1-methyl-5-[2-(6-methylsulfonylpyridin-3-yl)oxy-5-nitrophenyl]pyrrolidin-2-one
• CAS: 1616280-63-7
• 化学式: C₁₇H₁₇N₃O₆S
• 分子量: 391.404
• InChiKey: QSKIJUJTMZIWFD-UHFFFAOYSA-N

物化性质

• 沸点：
  596.1±50.0 °C(Predicted)
• 密度：
  1.408±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  131
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-methyl-5-(2-((6-(methylsulfonyl)pyridin-3-yl)oxy)-5-nitrophenyl)pyrrolidin-2-one 在 吡啶 、 盐酸 、 potassium iodate 、 铁粉 、 氯化铵 、 potassium iodide 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 异丙醇 为溶剂， 反应 16.92h， 生成 ethyl (2-iodo-5-(1-methyl-5-oxopyrrolidin-2-yl)-4-((6-(methylsulfonyl)pyridin-3-yl)oxy)phenyl)carbamate
  参考文献：
  名称：

  Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus

  摘要：

  Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic beta-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03 mg/kg led to robust blood glucose lowering efficacy in 3 week high fat diet-fed mice. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.10.085
• 作为产物：
  描述：

  2-氯-5-硝基苯甲醛 在 三丁基膦 、 叠氮磷酸二苯酯 、 水 、 sodium hydride 、 potassium carbonate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 三苯基膦 、 三氟乙酸 、 zinc(II) iodide 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 115.0h， 生成 1-methyl-5-(2-((6-(methylsulfonyl)pyridin-3-yl)oxy)-5-nitrophenyl)pyrrolidin-2-one
  参考文献：
  名称：

  Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus

  摘要：

  Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic beta-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03 mg/kg led to robust blood glucose lowering efficacy in 3 week high fat diet-fed mice. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.10.085

文献信息

• [EN] NOVEL GLUCOKINASE ACTIVATOR COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS, AND METHODS OF TREATMENT<br/>[FR] NOUVEAUX COMPOSÉS ACTIVATEURS DE GLUCOKINASE, COMPOSITIONS CONTENANT DE TELS COMPOSÉS, ET MÉTHODES DE TRAITEMENT
  申请人：MERCK SHARP & DOHME

  公开号：WO2014099578A1

  公开（公告）日：2014-06-26

  Novel pyridine-2-carboxamide derivatives of formula I: and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are effective as glucokinase activating agents. Pharmaceutical compositions and methods of treatment are also included.

  公开了式I的新型吡啶-2-羧酰胺衍生物及其药用盐，用于治疗或预防2型糖尿病和类似疾病。这些化合物作为葡萄糖激酶激活剂具有有效性。同时还包括药物组合物和治疗方法。
• NOVEL GLUCOKINASE ACTIVATOR COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS, AND METHODS OF TREATMENT
  申请人：PARMEE Emma R.

  公开号：US20150336991A1

  公开（公告）日：2015-11-26

  Novel pyridine-2-carboxamide derivatives of formula I: and pharmaceutically acceptable salts thereof are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. The compounds are effective as glucokinase activating agents. Pharmaceutical compositions and methods of treatment are also included.

  本发明公开了式I的新型吡啶-2-羧酰胺衍生物及其药学上可接受的盐，用于治疗或预防2型糖尿病和类似疾病。这些化合物作为葡萄糖激酶激活剂具有良好的治疗效果。此外，本发明还包括药物组合物和治疗方法。
• US9453038B2
  申请人：——

  公开号：US9453038B2

  公开（公告）日：2016-09-27
• Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus
  作者：Jiayi Xu、Songnian Lin、Robert W. Myers、George Addona、Joel P. Berger、Brian Campbell、Hsuan-shen Chen、Zhesheng Chen、George J. Eiermann、Nadine H. Elowe、Brian T. Farrer、Wen Feng、Qinghong Fu、Roman Kats-Kagan、Michael Kavana、Sunita Malkani、Daniel R. McMasters、Kaushik Mitra、Michele J. Pachanski、Xinchun Tong、Maria E. Trujillo、Libo Xu、Bei Zhang、Fengqi Zhang、Rui Zhang、Emma R. Parmee

  DOI：10.1016/j.bmcl.2016.10.085

  日期：2017.5

  Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic beta-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03 mg/kg led to robust blood glucose lowering efficacy in 3 week high fat diet-fed mice. (C) 2016 Published by Elsevier Ltd.