Tert-butyl 2-[1-(4-chlorobenzoyl)-2-methyl-5-(3-phenylmethoxypropoxy)indol-3-yl]acetate | 346424-22-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: Tert-butyl 2-[1-(4-chlorobenzoyl)-2-methyl-5-(3-phenylmethoxypropoxy)indol-3-yl]acetate
• CAS: 346424-22-4
• 化学式: C₃₂H₃₄ClNO₅
• 分子量: 548.079
• InChiKey: UOSCKGDVULCAMA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  66.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Tert-butyl 2-[1-(4-chlorobenzoyl)-2-methyl-5-(3-phenylmethoxypropoxy)indol-3-yl]acetate 在 palladium on activated charcoal 氢气 、 溶剂黄146 、 三氟乙酸 作用下， 以 乙酸乙酯 为溶剂， 反应 13.5h， 生成 [1-(4-Chloro-benzoyl)-5-(3-hydroxy-propoxy)-2-methyl-1H-indol-3-yl]-acetic acid
  参考文献：
  名称：

  Discovery of Novel Aldose Reductase Inhibitors Using a Protein Structure-Based Approach:  3D-Database Search Followed by Design and Synthesis

  摘要：

  Aldose reductase (AR) has been implicated in the etiology of diabetic complications. Due to the limited number of currently available drugs for the treatment of diabetic complications, we have carried out structure-based drug design and synthesis in an attempt to find new types of AR inhibitors. With the ADAM&EVE program, a three-dimensional database (ACD3D) was searched using the ligand binding site of the AR crystal structure. Out of 179 compounds selected through this search followed by visual inspection, 36 compounds were purchased and subjected to a biological assay. Ten compounds showed more than 40% inhibition of AR at a 15 mug/mL concentration. In a subsequent lead optimization, a series of analogues of the most active compound were synthesized based on the docking mode derived by ADAM&EVE. Many of these congeners exhibited higher activities compared to the mother compound. Indeed, the most potent, synthesized compound showed a -20-fold increase in inhibitory activity (IC50 = 0.21 vs 4.3 muM). Furthermore, a hydrophobic subsite was newly inferred, which would be useful for the design of inhibitors with improved affinity for AR.

  DOI：

  10.1021/jm000483h
• 作为产物：
  描述：

  4-氧代戊酸叔丁酯 在 palladium on activated charcoal potassium tert-butylate 、 氢气 、 sodium acetate 、 溶剂黄146 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 溶剂黄146 、 乙酸乙酯 、 甲苯 为溶剂， 20.0 ℃ 、385.06 kPa 条件下， 反应 64.33h， 生成 Tert-butyl 2-[1-(4-chlorobenzoyl)-2-methyl-5-(3-phenylmethoxypropoxy)indol-3-yl]acetate
  参考文献：
  名称：

  Discovery of Novel Aldose Reductase Inhibitors Using a Protein Structure-Based Approach:  3D-Database Search Followed by Design and Synthesis

  摘要：

  Aldose reductase (AR) has been implicated in the etiology of diabetic complications. Due to the limited number of currently available drugs for the treatment of diabetic complications, we have carried out structure-based drug design and synthesis in an attempt to find new types of AR inhibitors. With the ADAM&EVE program, a three-dimensional database (ACD3D) was searched using the ligand binding site of the AR crystal structure. Out of 179 compounds selected through this search followed by visual inspection, 36 compounds were purchased and subjected to a biological assay. Ten compounds showed more than 40% inhibition of AR at a 15 mug/mL concentration. In a subsequent lead optimization, a series of analogues of the most active compound were synthesized based on the docking mode derived by ADAM&EVE. Many of these congeners exhibited higher activities compared to the mother compound. Indeed, the most potent, synthesized compound showed a -20-fold increase in inhibitory activity (IC50 = 0.21 vs 4.3 muM). Furthermore, a hydrophobic subsite was newly inferred, which would be useful for the design of inhibitors with improved affinity for AR.

  DOI：

  10.1021/jm000483h