(4R,5S,6S,7R)-4,7-Dibenzyl-1,3-bis-cyclopropylmethyl-5,6-bis-(2-trimethylsilanyl-ethoxymethoxy)-[1,3]diazepan-2-one | 206853-76-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂卓
• 英文名称: (4R,5S,6S,7R)-4,7-Dibenzyl-1,3-bis-cyclopropylmethyl-5,6-bis-(2-trimethylsilanyl-ethoxymethoxy)-[1,3]diazepan-2-one
• 英文别名: (4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(cyclopropylmethyl)-5,6-bis(2-trimethylsilylethoxymethoxy)-1,3-diazepan-2-one
• CAS: 206853-76-1
• 化学式: C₃₉H₆₂N₂O₅Si₂
• 分子量: 695.103
• InChiKey: IXODWPCPRYCNMQ-RNATXAOGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.16
• 重原子数：
  48
• 可旋转键数：
  20
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  60.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4R,5S,6S,7R)-4,7-Dibenzyl-1,3-bis-cyclopropylmethyl-5,6-bis-(2-trimethylsilanyl-ethoxymethoxy)-[1,3]diazepan-2-one 在 盐酸 、 乙醚 作用下， 以 甲醇 为溶剂， 反应 12.0h， 以86%的产率得到XK234
  参考文献：
  名称：

  循环尿素 HIV 蛋白酶抑制剂的计算和实验低能构象

  摘要：

  影响柔性配体对受体亲和力的一个重要因素是获得结合构象所需的内部应变能。对于大多数生物学感兴趣的系统，计算完全平衡的结合和游离配体和受体构象的集合在计算上是不可能的；因此，将新结构作为给定受体的潜在高亲和力配体的定性评估可以受益于考虑配体的结合和未结合（通常是水性）低能几何形状以及它们的内能差异。尽管可以使用许多计算生成和评估小分子构象偏好的技术，比较计算和实验观察到的构象的复杂有机物研究数量有限。为了评估我们预测循环 HIV 蛋白酶 (HIV-1 PR) 抑制剂的先验偏好构象的能力，九个 4,7-bis(phen...

  DOI：

  10.1021/ja972357h
• 作为产物：
  描述：

  N-methoxy-N-methyl-(R)-N²-Cbz-phenylalaninamide 在 palladium dihydroxide lithium aluminium tetrahydride 、 [VCl3(thf)3] 、 铜 、 sodium hydride 、 N,N-二异丙基乙胺 、 锌 、 环己烯 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 76.0h， 生成 (4R,5S,6S,7R)-4,7-Dibenzyl-1,3-bis-cyclopropylmethyl-5,6-bis-(2-trimethylsilanyl-ethoxymethoxy)-[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

文献信息

• Cyclic HIV Protease Inhibitors:  Synthesis, Conformational Analysis, P2/P2‘ Structure−Activity Relationship, and Molecular Recognition of Cyclic Ureas
  作者：Patrick Y. S. Lam、Yu Ru、Prabhakar K. Jadhav、Paul E. Aldrich、George V. DeLucca、Charles J. Eyermann、Chong-Hwan Chang、George Emmett、Edward R. Holler、Wayne F. Daneker、Liangzhu Li、Pat N. Confalone、Robert J. McHugh、Qi Han、Renhua Li、Jay A. Markwalder、Steven P. Seitz、Thomas R. Sharpe、Lee T. Bacheler、Marlene M. Rayner、Ronald M. Klabe、Linyee Shum、Dean L. Winslow、David M. Kornhauser、David A. Jackson、Susan Erickson-Viitanen、C. Nicholas Hodge

  DOI：10.1021/jm9602571

  日期：1996.1.1

  X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其
• 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.
• Calculated and Experimental Low-Energy Conformations of Cyclic Urea HIV Protease Inhibitors
  作者：C. Nicholas Hodge、Patrick Y. S. Lam、Charles J. Eyermann、Prabhakar K. Jadhav、Y. Ru、Christina H. Fernandez、George V. De Lucca、Chong-Hwan Chang、Robert F. Kaltenbach、Edward R. Holler、Francis Woerner、Wayne F. Daneker、George Emmett、Joseph C. Calabrese、Paul E. Aldrich

  DOI：10.1021/ja972357h

  日期：1998.5.1

  limited number of studies of complex organics that compare calculated and experimentally observed conformations. To assess our ability to predict a priori favored conformations of cyclic HIV protease (HIV-1 PR) inhibitors, conformational minima for nine 4,7-bis(phen...

  影响柔性配体对受体亲和力的一个重要因素是获得结合构象所需的内部应变能。对于大多数生物学感兴趣的系统，计算完全平衡的结合和游离配体和受体构象的集合在计算上是不可能的；因此，将新结构作为给定受体的潜在高亲和力配体的定性评估可以受益于考虑配体的结合和未结合（通常是水性）低能几何形状以及它们的内能差异。尽管可以使用许多计算生成和评估小分子构象偏好的技术，比较计算和实验观察到的构象的复杂有机物研究数量有限。为了评估我们预测循环 HIV 蛋白酶 (HIV-1 PR) 抑制剂的先验偏好构象的能力，九个 4,7-bis(phen...