(S)-3-(3-amino-phenylethynyl)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-3-(3-amino-phenylethynyl)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide
• 英文别名: 3-[2-(3-aminophenyl)ethynyl]-5-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)benzamide
• 化学式: C₂₃H₂₄N₄O₃
• 分子量: 404.469
• InChiKey: JJZHLHHSBFBDFN-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  91.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-氯乙基甲基醚 、 (S)-3-(3-amino-phenylethynyl)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide 生成 3-[2-[3-(2-methoxyethylamino)phenyl]ethynyl]-5-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)benzamide
  参考文献：
  名称：

  Design and Synthesis of Acetylenyl Benzamide Derivatives as Novel Glucokinase Activators for the Treatment of T2DM

  摘要：

  Novel acetylenyl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucokinase activity stimulated by 10 mM glucose concentration and glucose uptake in rat hepatocytes. Lead optimization of an acetylenyl benzarmide series led to the discovery of several active compounds via in vitro enzyme assays (EC50 < 40 nM) and in vivo OGTT assays (AUC reduction > 40% at 50 mg/kg). Of the active compounds tested, 3-(3-amino-phenylethynyl)-5-(2methorry-1-methyl-ethorry)-N-(1-methyl-111-pyrazol-3-yl)-benzamide (19) was identified as a potent glucokinase activator exhibiting an EC50 of 27 nM and eliciting a 2.16-fold increase in glucose uptake. Compound 19 caused a glucose AUC reduction of 47.4% (30 mg/kg) in an OGTT study in C57BL/6J mice compared to 22.6% for sitagliptin (30 mg/kg). Single treatment of the compound 19 in C57BL/6J mice elicited basal glucose lowering activity without any significant evidence for hypoglycemia risk. Compound 19 was therefore selected as a candidate for further predinical development for the treatment of type 2 diabetes.

  DOI：

  10.1021/ml5004712
• 作为产物：
  描述：

  3-溴-5-羟基苯甲酸甲酯 在 bis-triphenylphosphine-palladium(II) chloride 、 偶氮二甲酸二异丙酯 、 四丁基氟化铵 、 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 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 生成 (S)-3-(3-amino-phenylethynyl)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide
  参考文献：
  名称：

  Design and Synthesis of Acetylenyl Benzamide Derivatives as Novel Glucokinase Activators for the Treatment of T2DM

  摘要：

  Novel acetylenyl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucokinase activity stimulated by 10 mM glucose concentration and glucose uptake in rat hepatocytes. Lead optimization of an acetylenyl benzarmide series led to the discovery of several active compounds via in vitro enzyme assays (EC50 < 40 nM) and in vivo OGTT assays (AUC reduction > 40% at 50 mg/kg). Of the active compounds tested, 3-(3-amino-phenylethynyl)-5-(2methorry-1-methyl-ethorry)-N-(1-methyl-111-pyrazol-3-yl)-benzamide (19) was identified as a potent glucokinase activator exhibiting an EC50 of 27 nM and eliciting a 2.16-fold increase in glucose uptake. Compound 19 caused a glucose AUC reduction of 47.4% (30 mg/kg) in an OGTT study in C57BL/6J mice compared to 22.6% for sitagliptin (30 mg/kg). Single treatment of the compound 19 in C57BL/6J mice elicited basal glucose lowering activity without any significant evidence for hypoglycemia risk. Compound 19 was therefore selected as a candidate for further predinical development for the treatment of type 2 diabetes.

  DOI：

  10.1021/ml5004712