(±)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-2-methoxyethanamine

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: (±)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-2-methoxyethanamine
• 英文别名: N-[[1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl]methyl]-2-methoxyethanamine
• 化学式: C₁₈H₂₈N₂O
• 分子量: 288.433
• InChiKey: YWJBFFLJYSZCJL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  24.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (±)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-2-methoxyethanamine 、 2-萘甲酸 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 19.5h， 以36%的产率得到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
• 作为产物：
  描述：

  2-茚醇 在 silica gel 、 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 96.42h， 生成 (±)-N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-2-methoxyethanamine
  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

• Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents
  作者：Damijan Knez、Boris Brus、Nicolas Coquelle、Izidor Sosič、Roman Šink、Xavier Brazzolotto、Janez Mravljak、Jacques-Philippe Colletier、Stanislav Gobec

  DOI：10.1016/j.bmc.2015.06.010

  日期：2015.8

  Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (A beta(1-42)), inhibits with sub-micromolar potency butyrylcholinesterase (IC50 = 215 nM), and also selectively complexes Cu2+. Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold. (C) 2015 Elsevier Ltd. All rights reserved.
• DISUBSTITUTED PIPERIDINE DERIVATIVES AS BUTYRYLCHOLINESTERASE INHIBITORS FOR USE IN THE TREATMENT OF ALZHEIMER
  申请人：Univerza V Ljubljani

  公开号：US20180086707A1

  公开（公告）日：2018-03-29

  This invention relates to new inhibitors of butyrylcholinesterase with general formulas I and II, where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the treatment of Alzheimer's disease and other forms of dementia.
• 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