dimethyl (2-[5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)-methyl]-1H-pyrrol-3-yl]-2-hydroxy-1-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]ethyl)phosphonate | 1449692-07-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: dimethyl (2-[5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)-methyl]-1H-pyrrol-3-yl]-2-hydroxy-1-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]ethyl)phosphonate
• 英文别名: 1-[5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]pyrrol-3-yl]-2-dimethoxyphosphoryl-2-[(1S,2S,4R)-1,3,3-trimethyl-2-bicyclo[2.2.1]heptanyl]ethanol
• CAS: 1449692-07-2
• 化学式: C₃₃H₄₃ClNO₄P
• 分子量: 584.135
• InChiKey: UCMIKXLWMFVIGR-GTLDFRRRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  40
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  60.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  dimethyl (2-[5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)-methyl]-1H-pyrrol-3-yl]-2-hydroxy-1-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]ethyl)phosphonate 在 magnesium bromide diethyl etherate 作用下， 以 1,4-二氧六环 为溶剂， 反应 72.0h， 以2.6 mg的产率得到5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-3-[(E)-2-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]ethenyl]-1H-pyrrole
  参考文献：
  名称：

  The Importance of Hydrogen Bonding and Aromatic Stacking to the Affinity and Efficacy of Cannabinoid Receptor CB₂ Antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528)

  摘要：

  Despite the therapeutic promise of the subnanomolar affinity cannabinoid CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphe nyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicydo [2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528, 1), little is known about its binding site interactions and no primary interaction site for 1 at CB2 has been identified. We report here the results of Glide docking studies in our cannabinoid CB2 inactive state model that were then tested via compound synthesis, binding, and functional assays. Our results show that the amide functional group of 1 is critical to its CB2 affinity and efficacy and that aromatic stacking interactions in the TMH5/6 aromatic cluster of CB2 are also important. Molecular modifications that increased the positive electrostatic potential in the region between the fenthyl and aromatic rings led to more efficacious compounds. This result is consistent with the EC-3 loop negatively charged amino acid, D275 (identified via Glide docking studies) acting as the primary interaction site for 1 and its analogues.

  DOI：

  10.1021/jm400070u
• 作为产物：
  描述：

  4-氯-3-甲基苯甲醛 在 lithium aluminium tetrahydride 、 正丁基锂 、 三甲基氯硅烷 、 sodium thiosulfate pentahydrate 、 sodium hydride 、 戴斯-马丁氧化剂 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 丙酮 、 甲苯 、 乙腈 、 mineral oil 为溶剂， 反应 23.7h， 生成 dimethyl (2-[5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)-methyl]-1H-pyrrol-3-yl]-2-hydroxy-1-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]ethyl)phosphonate 、 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-3-[(E)-2-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]ethenyl]-1H-pyrrole
  参考文献：
  名称：

  The Importance of Hydrogen Bonding and Aromatic Stacking to the Affinity and Efficacy of Cannabinoid Receptor CB₂ Antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528)

  摘要：

  Despite the therapeutic promise of the subnanomolar affinity cannabinoid CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphe nyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicydo [2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528, 1), little is known about its binding site interactions and no primary interaction site for 1 at CB2 has been identified. We report here the results of Glide docking studies in our cannabinoid CB2 inactive state model that were then tested via compound synthesis, binding, and functional assays. Our results show that the amide functional group of 1 is critical to its CB2 affinity and efficacy and that aromatic stacking interactions in the TMH5/6 aromatic cluster of CB2 are also important. Molecular modifications that increased the positive electrostatic potential in the region between the fenthyl and aromatic rings led to more efficacious compounds. This result is consistent with the EC-3 loop negatively charged amino acid, D275 (identified via Glide docking studies) acting as the primary interaction site for 1 and its analogues.

  DOI：

  10.1021/jm400070u