1-(3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid methylamide | 1151519-26-4

• 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: 1-(3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid methylamide
• 英文别名: Proline scaffold, 5；(2S)-1-(3,3-diphenylpropanoyl)-N-methylpyrrolidine-2-carboxamide
• CAS: 1151519-26-4
• 化学式: C₂₁H₂₄N₂O₂
• 分子量: 336.434
• InChiKey: FAEVERIELARHCN-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  3,3-二苯基丙酸 、 L-proline methylamide 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.05h， 以70%的产率得到1-(3,3-diphenyl-propionyl)-pyrrolidine-2-carboxylic acid methylamide
  参考文献：
  名称：

  Compounds Binding to the S2−S3 Pockets of Thrombin

  摘要：

  A set of compounds designed to bind to the S2-S3 pockets of thrombin was prepared. These compounds included examples with no interactions in the S1 pocket. Proline, a common P2 in many thrombin inhibitors, was combined with known P3 residues and P1 substituents of varying size and lipophilicity. Binding constants were determined using surface plasmon resonance (SPR) biosensor technology and were found to be in good agreement with results from an enzyme assay. A dramatic increase in affinity (100-1000 times) was seen for compounds incorporating an amino group capable of forming a hydrogen bond with gly216 in the protein backbone. The ligand efficiency was increased by including substituents that form stronger hydrophobic interactions with the P1 pocket. The binding mode was confirmed by X-ray analysis, which revealed the anticipated binding motif that included hydrogen bonds as well as a tightly bound water molecule. A QSAR model indicated that hydrogen bonding and lipophilicity were important for the prediction of binding constants. The results described here may have implications for how directed compound libraries for shallow protein pockets, like S2 and S3 in serine proteases, can be designed.

  DOI：

  10.1021/jm8011849

文献信息

• Compounds Binding to the S2−S3 Pockets of Thrombin
  作者：Mikael Nilsson、Markku Hämäläinen、Maria Ivarsson、Johan Gottfries、Yafeng Xue、Sebastian Hansson、Roland Isaksson、Tomas Fex

  DOI：10.1021/jm8011849

  日期：2009.5.14

  A set of compounds designed to bind to the S2-S3 pockets of thrombin was prepared. These compounds included examples with no interactions in the S1 pocket. Proline, a common P2 in many thrombin inhibitors, was combined with known P3 residues and P1 substituents of varying size and lipophilicity. Binding constants were determined using surface plasmon resonance (SPR) biosensor technology and were found to be in good agreement with results from an enzyme assay. A dramatic increase in affinity (100-1000 times) was seen for compounds incorporating an amino group capable of forming a hydrogen bond with gly216 in the protein backbone. The ligand efficiency was increased by including substituents that form stronger hydrophobic interactions with the P1 pocket. The binding mode was confirmed by X-ray analysis, which revealed the anticipated binding motif that included hydrogen bonds as well as a tightly bound water molecule. A QSAR model indicated that hydrogen bonding and lipophilicity were important for the prediction of binding constants. The results described here may have implications for how directed compound libraries for shallow protein pockets, like S2 and S3 in serine proteases, can be designed.