(3aS,4R,8R,8aS)-5-[[3-(1H-benzimidazol-2-ylmethylamino)-4-fluorophenyl]methyl]-4,8-dibenzyl-2,2-dimethyl-7-[[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one | 1053408-44-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: (3aS,4R,8R,8aS)-5-[[3-(1H-benzimidazol-2-ylmethylamino)-4-fluorophenyl]methyl]-4,8-dibenzyl-2,2-dimethyl-7-[[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one
• CAS: 1053408-44-8
• 化学式: C₅₁H₅₈FN₇O₄Si
• 分子量: 880.15
• InChiKey: PTFBGGYXJFYZCR-QBHAMJTBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.16
• 重原子数：
  64
• 可旋转键数：
  16
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (3aS,4R,8R,8aS)-5-[[3-(1H-benzimidazol-2-ylmethylamino)-4-fluorophenyl]methyl]-4,8-dibenzyl-2,2-dimethyl-7-[[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 (4R,5S,6S,7R)-1-[[3-(1H-benzimidazol-2-ylmethylamino)-4-fluoro-phenyl]methyl]-4,7-dibenzyl-5,6-dihydroxy-3-(1H-indazol-5-ylmethyl)-1,3-diazepan-2-one
  参考文献：
  名称：

  Nonsymmetric P2/P2‘ Cyclic Urea HIV Protease Inhibitors. Structure−Activity Relationship, Bioavailability, and Resistance Profile of Monoindazole-Substituted P2 Analogues

  摘要：

  Using the structural information gathered from the X-ray structures of various cyclic urea/ HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (K-i) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).

  DOI：

  10.1021/jm980103g
• 作为产物：
  描述：

  4-氟-3-硝基溴苄 在 palladium on activated charcoal potassium tert-butylate 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 25.0 ℃ 、206.84 kPa 条件下， 反应 48.0h， 生成 (3aS,4R,8R,8aS)-5-[[3-(1H-benzimidazol-2-ylmethylamino)-4-fluorophenyl]methyl]-4,8-dibenzyl-2,2-dimethyl-7-[[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]methyl]-3a,4,8,8a-tetrahydro-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one
  参考文献：
  名称：

  Nonsymmetric P2/P2‘ Cyclic Urea HIV Protease Inhibitors. Structure−Activity Relationship, Bioavailability, and Resistance Profile of Monoindazole-Substituted P2 Analogues

  摘要：

  Using the structural information gathered from the X-ray structures of various cyclic urea/ HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (K-i) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).

  DOI：

  10.1021/jm980103g