tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carboxylate

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carboxylate
• 英文别名: tert-butyl 3-(4-methoxyphenyl)sulfanyl-6-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carboxylate
• 化学式: C₂₀H₂₂N₄O₃S₂
• 分子量: 430.552
• InChiKey: GCOKCEAATLIPRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  130
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carboxylate 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 Ethyl ({2-[({3-[(4-methoxyphenyl)sulfanyl]-6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]pyridin-2-yl}carbonyl)amino]-1,3-thiazol-5-yl}sulfanyl)acetate
  参考文献：
  名称：

  Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus

  摘要：

  Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic beta-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose -lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses >= 10 mpk, with >= 70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.10.088
• 作为产物：
  描述：

  2-氯-5-氟吡啶-6-羧酸 在 三氟化硼乙醚 、 potassium tert-butylate 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-6-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carboxylate
  参考文献：
  名称：

  Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus

  摘要：

  Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic beta-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose -lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses >= 10 mpk, with >= 70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia. (C) 2016 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2016.10.088

文献信息

• NOVEL 2-PYRIDINECARBOXAMIDE DERIVATIVES, COMPOSITIONS CONTAINING SUCH COMPOUNDS, AND METHODS OF TREATMENT
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US20150336946A1

  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. The present invention relates to novel pyridine-2-carboxamide derivatives and salts thereof which are effective as glucokinase activating agents. Moreover, it relates to compositions containing such compounds, and methods of treatment.

  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有效性。本发明还涉及包含这些化合物的制药组合物和治疗方法。本发明涉及新型吡啶-2-羧酰胺衍生物及其盐，其作为葡萄糖激酶激活剂具有有效性。此外，涉及含有此类化合物的组合物和治疗方法。
• US9527838B2
  申请人：——

  公开号：US9527838B2

  公开（公告）日：2016-12-27
• [EN] NOVEL 2-PYRIDINECARBOXAMIDE DERIVATIVES, COMPOSITIONS CONTAINING SUCH COMPOUNDS, AND METHODS OF TREATMENT<br/>[FR] NOUVEAUX DÉRIVÉS DE PYRIDINE -2-CARBOXAMIDE, COMPOSITIONS CONTENANT DE TELS COMPOSÉS ET MÉTHODES DE TRAITEMENT ASSOCIÉES
  申请人：MERCK SHARP & DOHME

  公开号：WO2014099584A1

  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. The present invention relates to novel pyridine-2-carboxamide derivatives and salts thereof which are effective as glucokinase activating agents. Moreover, it relates to compositions containing such compounds, and methods of treatment.
• Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus
  作者：Jiayi Xu、Songnian Lin、Robert W. Myers、Maria E. Trujillo、Michele J. Pachanski、Sunita Malkani、Hsuan-shen Chen、Zhesheng Chen、Brian Campbell、George J. Eiermann、Nadine Elowe、Brian T. Farrer、Wen Feng、Qinghong Fu、Roman Kats-Kagan、Michael Kavana、Daniel R. McMasters、Kaushik Mitra、Xinchun Tong、Libo Xu、Fengqi Zhang、Rui Zhang、George H. Addona、Joel P. Berger、Bei Zhang、Emma R. Parmee

  DOI：10.1016/j.bmcl.2016.10.088

  日期：2017.5

  Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic beta-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose -lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses >= 10 mpk, with >= 70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia. (C) 2016 Published by Elsevier Ltd.