N-[(2S,3R)-4-[[(4S)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-(3-prop-2-enylphenyl)butan-2-yl]-6-oxo-1-prop-2-enyl-5-pyridin-2-ylpyridine-3-carboxamide | 939408-09-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: N-[(2S,3R)-4-[[(4S)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-(3-prop-2-enylphenyl)butan-2-yl]-6-oxo-1-prop-2-enyl-5-pyridin-2-ylpyridine-3-carboxamide
• CAS: 939408-09-0
• 化学式: C₄₁H₄₆N₄O₄
• 分子量: 658.841
• InChiKey: IFYMCHZGKHNAPX-AGSXMJPOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  49
• 可旋转键数：
  14
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-[(2S,3R)-4-[[(4S)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-(3-prop-2-enylphenyl)butan-2-yl]-6-oxo-1-prop-2-enyl-5-pyridin-2-ylpyridine-3-carboxamide 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 苯 为溶剂， 23.0 ℃ 、101.33 kPa 条件下， 生成 (12S)-12-[(1R)-2-[[(4S)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-1-hydroxyethyl]-17-pyridin-2-yl-1,13-diazatricyclo[13.3.1.16,10]icosa-6(20),7,9,15(19),16-pentaene-14,18-dione
  参考文献：
  名称：

  Hydroxyethylamine-based inhibitors of BACE1: P1–P3 macrocyclization can improve potency, selectivity, and cell activity

  摘要：

  We describe a systematic study of how macrocyclization in the P-1-P-3 region of hydroxyethylamine-based inhibitors of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid beta-peptide (A beta)-lowering activity in HEK293T cells stably expressing APP(SW). However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.028
• 作为产物：
  描述：

  (3-bromobenzyl)magnesium bromide 在 盐酸 、 四(三苯基膦)钯 、 1,3-二甲基巴比妥酸 、 potassium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 tetramethylammonium triacetoxyborohydride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 乙醇 、 二氯甲烷 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-[(2S,3R)-4-[[(4S)-6-ethylspiro[3,4-dihydrochromene-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-(3-prop-2-enylphenyl)butan-2-yl]-6-oxo-1-prop-2-enyl-5-pyridin-2-ylpyridine-3-carboxamide
  参考文献：
  名称：

  Hydroxyethylamine-based inhibitors of BACE1: P1–P3 macrocyclization can improve potency, selectivity, and cell activity

  摘要：

  We describe a systematic study of how macrocyclization in the P-1-P-3 region of hydroxyethylamine-based inhibitors of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid beta-peptide (A beta)-lowering activity in HEK293T cells stably expressing APP(SW). However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.028