KMI-1256 | 1160850-86-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: KMI-1256
• 英文别名: N-((2S,3S)-4-(3-(2H-tetrazol-5-yl)phenylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-4-bromo-6-((S)-4-phenyloxazolidine-3-carbonyl)picolinamide；4-bromo-N-[(2S,3S)-3-hydroxy-4-oxo-1-phenyl-4-[3-(2H-tetrazol-5-yl)anilino]butan-2-yl]-6-[(4S)-4-phenyl-1,3-oxazolidine-3-carbonyl]pyridine-2-carboxamide
• CAS: 1160850-86-1
• 化学式: C₃₃H₂₉BrN₈O₅
• 分子量: 697.548
• InChiKey: VJRDPWORFMXZOD-OYFGVDPJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  47
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  175
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (2S,3S)-3-amino-2-hydroxy-4-phenyl-N-[3-(2H-tetrazol-5-yl)phenyl]butanamide 、 (S)-4-bromo-6-(4-phenyloxazolidine-3-carbonyl)picolinic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 KMI-1256
  参考文献：
  名称：

  Significance of interactions of BACE1–Arg235 with its ligands and design of BACE1 inhibitors with P2 pyridine scaffold

  摘要：

  Recently, we reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Because these inhibitors contained some natural amino acids, we would need to improve their enzymatic stability in vivo and permeability across the blood-brain barrier, so that they become practically useful. Subsequently, non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold, 2,6-pyridenedicarboxylic, chelidamic or chelidonic moiety, at the P-2 position were reported. These inhibitors were designed based on the conformer of docked inhibitor in BACE1. In this study, we discuss the role and significance of interactions between Arg235 of BACE1 and its inhibitor in BACE1 inhibitory mechanism. Moreover, we designed more potent small-sized BACE1 inhibitors with a 2,6-pyridinedicarboxylic scaffold at the P2 position, that were optimized for the interactions with Arg235 of BACE1. (c) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.03.049