ethyl 1-(4-cyanophenyl)-5-(propylthio)-1H-pyrazole-4-carboxylate | 1407516-24-8

• 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 1-(4-cyanophenyl)-5-(propylthio)-1H-pyrazole-4-carboxylate
• 英文别名: Ethyl 1-(4-cyanophenyl)-5-propylsulfanylpyrazole-4-carboxylate；ethyl 1-(4-cyanophenyl)-5-propylsulfanylpyrazole-4-carboxylate
• CAS: 1407516-24-8
• 化学式: C₁₆H₁₇N₃O₂S
• 分子量: 315.396
• InChiKey: VYXNIOHWSGZYJX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  93.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 1-(4-cyanophenyl)-5-(propylthio)-1H-pyrazole-4-carboxylate 在 potassium trimethylsilonate 、 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 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 52.0h， 生成 4-[4-[((trans)-5-methoxy-2-adamantyl)carbamoyl]-5-propylsulfanyl-pyrazol-1-yl]benzoic acid
  参考文献：
  名称：

  Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)

  摘要：

  Inhibition of 11 beta-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.

  DOI：

  10.1021/jm301252n
• 作为产物：
  描述：

  4-氰基苯肼盐酸盐 在 亚硝酸特丁酯 、 sodium carbonate 、 三乙胺 、 copper dichloride 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 22.5h， 生成 ethyl 1-(4-cyanophenyl)-5-(propylthio)-1H-pyrazole-4-carboxylate
  参考文献：
  名称：

  Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)

  摘要：

  Inhibition of 11 beta-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.

  DOI：

  10.1021/jm301252n

文献信息

• Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4-[4-(2-Adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)
  作者：James S. Scott、Joanne deSchoolmeester、Elaine Kilgour、Rachel M. Mayers、Martin J. Packer、David Hargreaves、Stefan Gerhardt、Derek J. Ogg、Amanda Rees、Nidhal Selmi、Andrew Stocker、John G. Swales、Paul R. O. Whittamore

  DOI：10.1021/jm301252n

  日期：2012.11.26

  Inhibition of 11 beta-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.