isopropyl 2-(3-acetyl-5-((2S,3R)-4-(3-fluorophenylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-2,4,6-trimethylpyridin-1(4H)-yl)acetate | 1229575-68-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: isopropyl 2-(3-acetyl-5-((2S,3R)-4-(3-fluorophenylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-2,4,6-trimethylpyridin-1(4H)-yl)acetate
• 英文别名: propan-2-yl 2-[3-acetyl-5-[[(2S,3R)-4-(3-fluoroanilino)-3-hydroxy-1-phenylbutan-2-yl]carbamoyl]-2,4,6-trimethyl-4H-pyridin-1-yl]acetate
• CAS: 1229575-68-1
• 化学式: C₃₂H₄₀FN₃O₅
• 分子量: 565.685
• InChiKey: LGSJTMUEVUBNRI-MDVVCPKYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  、 5-acetyl-2,4,6-trimethyl-1-(2-oxo-2-propan-2-yloxyethyl)-4H-pyridine-3-carboxylic acid 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11%的产率得到isopropyl 2-(3-acetyl-5-((2S,3R)-4-(3-fluorophenylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-2,4,6-trimethylpyridin-1(4H)-yl)acetate
  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.