3-{(3S,5R)-5-Benzyl-1-[(2S,4R)-2-hydroxy-4-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-5-phenyl-pentyl]-2-oxo-pyrrolidin-3-ylmethyl}-benzoic acid methyl ester | 809278-82-8

• 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: 3-{(3S,5R)-5-Benzyl-1-[(2S,4R)-2-hydroxy-4-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-5-phenyl-pentyl]-2-oxo-pyrrolidin-3-ylmethyl}-benzoic acid methyl ester
• 英文别名: Methyl 3-[(1-{4-[N-((1S,2R)-2-hydroxyindanyl)carbamoyl](2S,4R)-2-hydroxy-5-phenylpentyl}(3S,5R)-2-oxo-5-benzylpyrrolidin-3-yl)methyl]benzoate；methyl 3-[[(3S,5R)-5-benzyl-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl]-2-oxopyrrolidin-3-yl]methyl]benzoate
• CAS: 809278-82-8
• 化学式: C₄₁H₄₄N₂O₆
• 分子量: 660.81
• InChiKey: GRNIIDHVCJYQIT-UFCOSCRDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  49
• 可旋转键数：
  14
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  二甘醇胺 、 3-{(3S,5R)-5-Benzyl-1-[(2S,4R)-2-hydroxy-4-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-5-phenyl-pentyl]-2-oxo-pyrrolidin-3-ylmethyl}-benzoic acid methyl ester 生成 3-{(3S,5R)-5-Benzyl-1-[(2S,4R)-2-hydroxy-4-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-5-phenyl-pentyl]-2-oxo-pyrrolidin-3-ylmethyl}-N-[2-(2-hydroxy-ethoxy)-ethyl]-benzamide
  参考文献：
  名称：

  Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties

  摘要：

  We have developed efficient syntheses of the HIV-1 protease inhibitor 4 and its analogues, which incorporate the pyrrolidone scaffold 2 as P1-P2 moiety. Evaluation of these analogues in the HIV-1 protease enzyme assay resulted in discovery of potent and more water soluble meta-amino- and meta-hydroxy inhibitors 17b and 19b. The SAR observed in this class of PIs could be rationalized with aid of the X-ray structure of inhibitor 28 co-crystallized with the HIV-1 protease, which suggested that the polar meta- (but not para-) benzyl substituents in P2 could side-step the hydrophobic S2 enzyme active pocket by rotating the P2 moiety around its Cbeta-Cgamma bond. Such reorientation allows to engage the unsubstituted, hydrophobic edge of benzyl moiety in P2 in the requisite P2/S2 hydrophobic interaction, and projects polar meta-substituent into the bound water. It appears that the meta-position can be chemically derivatized without potency loss of thus resulting inhibitors, as evidenced by potent 22-26. We thus identified pyrrolidone 2-based inhibitors exemplified by 17b and 19b, which uniquely accommodate both high enzyme potency and which provide a platform for fine-tuning of drug-like properties in this class of PIs by additional chemical manipulations on the meta-position. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.08.039
• 作为产物：
  描述：

  (R)-2-氧代-5-苄基-1-吡咯烷羧酸叔丁酯 在 盐酸 、 P₄-phospazine 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 生成 3-{(3S,5R)-5-Benzyl-1-[(2S,4R)-2-hydroxy-4-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-5-phenyl-pentyl]-2-oxo-pyrrolidin-3-ylmethyl}-benzoic acid methyl ester
  参考文献：
  名称：

  Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties

  摘要：

  We have developed efficient syntheses of the HIV-1 protease inhibitor 4 and its analogues, which incorporate the pyrrolidone scaffold 2 as P1-P2 moiety. Evaluation of these analogues in the HIV-1 protease enzyme assay resulted in discovery of potent and more water soluble meta-amino- and meta-hydroxy inhibitors 17b and 19b. The SAR observed in this class of PIs could be rationalized with aid of the X-ray structure of inhibitor 28 co-crystallized with the HIV-1 protease, which suggested that the polar meta- (but not para-) benzyl substituents in P2 could side-step the hydrophobic S2 enzyme active pocket by rotating the P2 moiety around its Cbeta-Cgamma bond. Such reorientation allows to engage the unsubstituted, hydrophobic edge of benzyl moiety in P2 in the requisite P2/S2 hydrophobic interaction, and projects polar meta-substituent into the bound water. It appears that the meta-position can be chemically derivatized without potency loss of thus resulting inhibitors, as evidenced by potent 22-26. We thus identified pyrrolidone 2-based inhibitors exemplified by 17b and 19b, which uniquely accommodate both high enzyme potency and which provide a platform for fine-tuning of drug-like properties in this class of PIs by additional chemical manipulations on the meta-position. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.08.039