benzyl 5-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-2,6-dimethyl-1-(methylsulfonyl)-4-phenyl-1,4-dihydropyridine-3-carboxylate | 1229575-62-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl 5-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-2,6-dimethyl-1-(methylsulfonyl)-4-phenyl-1,4-dihydropyridine-3-carboxylate
• 英文别名: benzyl 5-[[(2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl]carbamoyl]-2,6-dimethyl-1-methylsulfonyl-4-phenyl-4H-pyridine-3-carboxylate
• CAS: 1229575-62-5
• 化学式: C₃₆H₄₁N₃O₆S
• 分子量: 643.804
• InChiKey: MHXSLVXBYSAWSE-ABKFLVSBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  46
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  133
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,6-dimethyl-1-methylsulfonyl-4-phenyl-5-phenylmethoxycarbonyl-4H-pyridine-3-carboxylic acid 、 (2R,3S)-3-amino-1-(cyclopropylamino)-4-phenylbutan-2-ol 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 以62.6%的产率得到benzyl 5-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-2,6-dimethyl-1-(methylsulfonyl)-4-phenyl-1,4-dihydropyridine-3-carboxylate
  参考文献：
  名称：

  Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors

  摘要：

  BACE-1 has been shown to be an attractive therapeutic target in Alzheimer's disease (AD). Using a 1,4-dihydropyridine (DHP) scaffold, we synthesized new inhibitors of BACE-1 by modifying the known BACE inhibitor 2 containing a hydroxyethylamine (HEA) motif. Using structure-based drug design based on computer-aided molecular docking, the isophthalamide ring of 2 was replaced with a 1,4-dihydropyridine ring as a brain-targeting strategy. Several of the new dihydropyridine derivatives were synthesized and their BACE-1-inhibitory activities were evaluated using a cell-based, reporter gene assay system that measures the cleavage of alkaline phosphatase (AP)-APP fusion protein by BACE-1. Most of the 1,4-DHP analogs showed BACE-1-inhibitory activities with IC50 values in the range 8-30 mu M, suggesting that the 1,4-DHP skeleton may be utilized to develop brain-targeting BACE-1 inhibitors.

  DOI：

  10.1016/j.ejmech.2010.02.046

文献信息

• Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors
  作者：Soo-Jeong Choi、Joong-Heui Cho、Isak Im、So-Deok Lee、Ji-Yeon Jang、Yu-Min Oh、Yong-Keun Jung、Eun-Seok Jeon、Yong-Chul Kim

  DOI：10.1016/j.ejmech.2010.02.046

  日期：2010.6

  BACE-1 has been shown to be an attractive therapeutic target in Alzheimer's disease (AD). Using a 1,4-dihydropyridine (DHP) scaffold, we synthesized new inhibitors of BACE-1 by modifying the known BACE inhibitor 2 containing a hydroxyethylamine (HEA) motif. Using structure-based drug design based on computer-aided molecular docking, the isophthalamide ring of 2 was replaced with a 1,4-dihydropyridine ring as a brain-targeting strategy. Several of the new dihydropyridine derivatives were synthesized and their BACE-1-inhibitory activities were evaluated using a cell-based, reporter gene assay system that measures the cleavage of alkaline phosphatase (AP)-APP fusion protein by BACE-1. Most of the 1,4-DHP analogs showed BACE-1-inhibitory activities with IC50 values in the range 8-30 mu M, suggesting that the 1,4-DHP skeleton may be utilized to develop brain-targeting BACE-1 inhibitors.