N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)-methyl)-N-(2-methoxyethyl)-2-naphthamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)-methyl)-N-(2-methoxyethyl)-2-naphthamide
• 英文别名: N-[[1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl]methyl]-N-(2-methoxyethyl)naphthalene-2-carboxamide
• 化学式: C₂₉H₃₄N₂O₂
• 分子量: 442.601
• InChiKey: NRBCHFHGWACYAH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-茚醇 在 silica gel 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 pyridinium chlorochromate 、 三氟乙酸 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 115.92h， 生成 N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)-methyl)-N-(2-methoxyethyl)-2-naphthamide
  参考文献：
  名称：

  Discovery, Biological Evaluation, and Crystal Structure of a Novel Nanomolar Selective Butyrylcholinesterase Inhibitor

  摘要：

  Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent compound 1 (IC50 = 21.3 nM) was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed and a dissociation constant of 2.7 nM was determined for the most potent steroisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved revealing the binding mode and providing clues for potential optimization additionally,compound 1 inhibited amyloid (beta)1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 mu M) and protected cultured SH-SYSY cells against amyloid-beta-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit to-lead follow up in the drug-discovery process against Alzheimer's disease

  DOI：

  10.1021/jm501195e

文献信息

• Discovery, Biological Evaluation, and Crystal Structure of a Novel Nanomolar Selective Butyrylcholinesterase Inhibitor
  作者：Boris Brus、Urban Košak、Samo Turk、Anja Pišlar、Nicolas Coquelle、Janko Kos、Jure Stojan、Jacques-Philippe Colletier、Stanislav Gobec

  DOI：10.1021/jm501195e

  日期：2014.10.9

  Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent compound 1 (IC50 = 21.3 nM) was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed and a dissociation constant of 2.7 nM was determined for the most potent steroisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved revealing the binding mode and providing clues for potential optimization additionally,compound 1 inhibited amyloid (beta)1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 mu M) and protected cultured SH-SYSY cells against amyloid-beta-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit to-lead follow up in the drug-discovery process against Alzheimer's disease