2-(4-(4'-methoxybiphenyl-3-ylsulfonyl)piperazin-1-yl)-3-(4-methoxyphenyl)pyrazine | 1377550-22-5

• 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: 2-(4-(4'-methoxybiphenyl-3-ylsulfonyl)piperazin-1-yl)-3-(4-methoxyphenyl)pyrazine
• 英文别名: 2-{4-[(4'-Methoxybiphenyl-3-Yl)sulfonyl]piperazin-1-Yl}-3-(4-Methoxyphenyl)pyrazine；2-(4-methoxyphenyl)-3-[4-[3-(4-methoxyphenyl)phenyl]sulfonylpiperazin-1-yl]pyrazine
• CAS: 1377550-22-5
• 化学式: C₂₈H₂₈N₄O₄S
• 分子量: 516.621
• InChiKey: IQVDMFYVPSHFEP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  93.2
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-溴苯磺酰氯 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 2.5h， 生成 2-(4-(4'-methoxybiphenyl-3-ylsulfonyl)piperazin-1-yl)-3-(4-methoxyphenyl)pyrazine
  参考文献：
  名称：

  Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase γ Inhibitors

  摘要：

  The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3K gamma to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3K gamma revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.

  DOI：

  10.1021/jm300403a

文献信息

• Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase γ Inhibitors
  作者：James W. Leahy、Chris A. Buhr、Henry W. B. Johnson、Byung Gyu Kim、TaeGon Baik、Jonah Cannoy、Timothy P. Forsyth、Joon Won Jeong、Matthew S. Lee、Sunghoon Ma、Kevin Noson、Longcheng Wang、Matthew Williams、John M. Nuss、Eric Brooks、Paul Foster、Leanne Goon、Nathan Heald、Charles Holst、Christopher Jaeger、Scott Lam、Julie Lougheed、Lam Nguyen、Arthur Plonowski、Joanne Song、Thomas Stout、Xiang Wu、Michael F. Yakes、Peiwen Yu、Wentao Zhang、Peter Lamb、Olivia Raeber

  DOI：10.1021/jm300403a

  日期：2012.6.14

  The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3K gamma to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3K gamma revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.