7-ethoxy-3-methyl-1H-indazole-5-carboxylic acid | 1287246-27-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: 7-ethoxy-3-methyl-1H-indazole-5-carboxylic acid
• 英文别名: 7-ethoxy-3-methyl-2H-indazole-5-carboxylic acid
• CAS: 1287246-27-8
• 化学式: C₁₁H₁₂N₂O₃
• 分子量: 220.228
• InChiKey: AUWMXDSDQZSZPU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  75.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-ethoxy-3-methyl-1H-indazole-5-carboxylic acid 、 2'-ethyl-3'-methyl-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one hydrochloride 在 N-甲基吗啉 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 作用下， 反应 1.0h， 以43%的产率得到1-(7-ethoxy-3-methyl-1H-indazole-5-carbonyl)-2'-ethyl-3'-methyl-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one
  参考文献：
  名称：

  Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

  摘要：

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

  DOI：

  10.1021/jm201503u
• 作为产物：
  描述：

  ethyl 7-hydroxy-3-methyl-1H-indazole-5-carboxylate 在 sodium hydride 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 1.0h， 生成 7-ethoxy-3-methyl-1H-indazole-5-carboxylic acid
  参考文献：
  名称：

  Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

  摘要：

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

  DOI：

  10.1021/jm201503u

文献信息

• Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase
  作者：Kevin D. Freeman-Cook、Paul Amor、Scott Bader、Leanne M. Buzon、Steven B. Coffey、Jeffrey W. Corbett、Kenneth J. Dirico、Shawn D. Doran、Richard L. Elliott、William Esler、Angel Guzman-Perez、Kevin E. Henegar、Janet A. Houser、Christopher S. Jones、Chris Limberakis、Katherine Loomis、Kirk McPherson、Sharad Murdande、Kendra L. Nelson、Dennis Phillion、Betsy S. Pierce、Wei Song、Eliot Sugarman、Susan Tapley、Meihua Tu、Zhengrong Zhao

  DOI：10.1021/jm201503u

  日期：2012.1.26

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.