1-(2,4-dimethyl-1H-benzo[d]imidazole-6-carbonyl)-2'-ethyl-3'-methyl-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one | 1197941-32-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-(2,4-dimethyl-1H-benzo[d]imidazole-6-carbonyl)-2'-ethyl-3'-methyl-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one
• 英文别名: 1-(2,4-dimethyl-1H-benzo[d]imidazole-6-ylcarbonyl)-2'-ethyl-3'-methyl-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one；1'-(2,7-dimethyl-3H-benzimidazole-5-carbonyl)-2-ethyl-3-methylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one
• CAS: 1197941-32-4
• 化学式: C₂₃H₂₇N₅O₃
• 分子量: 421.499
• InChiKey: IBCRHLILVFYVJT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  31
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  93.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-溴-3-甲基苯-1,2-二胺 在 N-甲基吗啉 、 盐酸 、 trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 、 molybdenum hexacarbonyl 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 2.34h， 生成 1-(2,4-dimethyl-1H-benzo[d]imidazole-6-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

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.