(3aS,4R,8R,8aS)-5,7-dibenzyl-2,2-dimethyl-4,8-bis[(4-methylsulfanylphenyl)methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one | 177284-12-7

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: (3aS,4R,8R,8aS)-5,7-dibenzyl-2,2-dimethyl-4,8-bis[(4-methylsulfanylphenyl)methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one
• CAS: 177284-12-7
• 化学式: C₃₈H₄₂N₂O₃S₂
• 分子量: 638.895
• InChiKey: FFIWHVMPRVRZGR-NWJWHWDBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.9
• 重原子数：
  45
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  92.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3aS,4R,8R,8aS)-5,7-dibenzyl-2,2-dimethyl-4,8-bis[(4-methylsulfanylphenyl)methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one 在 盐酸 作用下， 以 乙腈 为溶剂， 反应 2.0h， 以95%的产率得到(4R,5S,6S,7R)-1,3-dibenzyl-5,6-dihydroxy-4,7-bis[(4-methylsulfanylphenyl)methyl]-1,3-diazepan-2-one
  参考文献：
  名称：

  Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors

  摘要：

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

  DOI：

  10.1021/jm960083n
• 作为产物：
  描述：

  (1S)-1-[(4S,5S)-5-[(1S)-1-hydroxy-2-(4-methylsulfanylphenyl)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(4-methylsulfanylphenyl)ethanol 在 lithium aluminium tetrahydride 、 叠氮磷酸二苯酯 、 sodium hydride 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 4.08h， 生成 (3aS,4R,8R,8aS)-5,7-dibenzyl-2,2-dimethyl-4,8-bis[(4-methylsulfanylphenyl)methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one
  参考文献：
  名称：

  Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors

  摘要：

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

  DOI：

  10.1021/jm960083n

文献信息

• Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors
  作者：David A. Nugiel、Kim Jacobs、Tabitha Worley、Mona Patel、Robert F. Kaltenbach、Dayton T. Meyer、Prabhakar K. Jadhav、George V. De Lucca、Thomas E. Smyser、Ronald M. Klabe、Lee T. Bacheler、Marlene M. Rayner、Steven P. Seitz

  DOI：10.1021/jm960083n

  日期：1996.1.1

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.