(1S)-1-[(4S,5S)-5-[(1S)-1-hydroxy-2-naphthalen-2-ylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-naphthalen-2-ylethanol | 177284-05-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (1S)-1-[(4S,5S)-5-[(1S)-1-hydroxy-2-naphthalen-2-ylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-naphthalen-2-ylethanol
• CAS: 177284-05-8
• 化学式: C₂₉H₃₀O₄
• 分子量: 442.555
• InChiKey: VYNIWVLGWIYKAS-LJWNLINESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  58.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1S)-1-[(4S,5S)-5-[(1S)-1-hydroxy-2-naphthalen-2-ylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-naphthalen-2-ylethanol 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-bis(cyclopropylmethyl)-2,2-dimethyl-4,8-bis(naphthalen-2-ylmethyl)-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
• 作为产物：
  描述：

  1,2:3,4:5,6-tri-O-isopropylidene-L-mannitol 在 正丁基锂 、 copper(l) cyanide 、 溶剂黄146 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 甲苯 为溶剂， 反应 3.0h， 生成 (1S)-1-[(4S,5S)-5-[(1S)-1-hydroxy-2-naphthalen-2-ylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-naphthalen-2-ylethanol
  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

• Improved P1/P1‘ Substituents for Cyclic Urea Based HIV-1 Protease Inhibitors:  Synthesis, Structure−Activity Relationship, and X-ray Crystal Structure Analysis
  作者：David A. Nugiel、Kim Jacobs、Lyndon Cornelius、Chong-Hwan Chang、Prabhakar K. Jadhav、Edward R. Holler、Ronald M. Klabe、Lee T. Bacheler、Beverly Cordova、Sena Garber、Carol Reid、Kelly A. Logue、Lorraine J. Gorey-Feret、Gilbert N. Lam、Susan Erickson-Viitanen、Steven P. Seitz

  DOI：10.1021/jm960839i

  日期：1997.5.1

  facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic

  我们提出了几种新颖的P1 / P1'取代基，它们可以取代基于环脲的HIV蛋白酶抑制剂系列的特征性苄基P1 / P1'部分。与未取代的苄基类似物相比，这些取代基通常提供5-10倍的结合亲和力。最好的取代基是3，4-（亚乙二氧基）苄基。分子亲脂性的适当平衡促进了这种改善的结合亲和力向优良细胞抗病毒活性谱的转移。进一步评估了几种类似物的蛋白质结合和抗药性。根据化合物18的log P和溶解度曲线，选择其化合物18（IC90 = 8.7 nM）进行口服生物利用度研究。狗的10 mg / kg剂量具有适度的生物利用度，Cmax = 0.22 microg / mL。两种类似物的X射线晶体学分析揭示了3,4-（乙二氧基）苄基取代的类似物的效力的几个有趣特征：（1）比较这两种络合物，发现每个P1 / P1'取代基有两种不同的结合方式；（2）乙二氧基部分在Pro 81的3.6 A之内，可提供母体结构中缺少的更多范德华接触；（3）酶的Arg