N-((S)-2-amino-3-((S)-1-((S)-1-((2S,3R)-3-hydroxy-4-oxo-1-phenyl-4-(1-phenylcyclohexylamino)butan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxobutan-2-ylamino)-3-oxopropyl)-2,5-dihydroxybenzamide | 1333494-93-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: N-((S)-2-amino-3-((S)-1-((S)-1-((2S,3R)-3-hydroxy-4-oxo-1-phenyl-4-(1-phenylcyclohexylamino)butan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxobutan-2-ylamino)-3-oxopropyl)-2,5-dihydroxybenzamide
• 英文别名: KMI-1771；N-[(2S)-2-amino-3-[[(2S)-1-[[(2S)-1-[[(2S,3R)-3-hydroxy-4-oxo-1-phenyl-4-[(1-phenylcyclohexyl)amino]butan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-oxopropyl]-2,5-dihydroxybenzamide
• CAS: 1333494-93-1
• 化学式: C₄₃H₅₈N₆O₈
• 分子量: 786.969
• InChiKey: MEADKDZQPOPREB-YOUWDLPQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  57
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  232
• 氢给体数：
  9
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1-苯基-1-环己醇 在 盐酸 、 lithium aluminium tetrahydride 、 sodium azide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 二乙胺 、 三乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 68.25h， 生成 N-((S)-2-amino-3-((S)-1-((S)-1-((2S,3R)-3-hydroxy-4-oxo-1-phenyl-4-(1-phenylcyclohexylamino)butan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxobutan-2-ylamino)-3-oxopropyl)-2,5-dihydroxybenzamide
  参考文献：
  名称：

  Structure-guided design and synthesis of P1′ position 1-phenylcycloalkylamine-derived pentapeptidic BACE1 inhibitors

  摘要：

  Previously, we reported potent pentapeptidic BACE1 inhibitors with the hydroxymethylcarbonyl isostere as a substrate transition-state mimic. To improve the in vitro potency, we further reported pentapeptidic inhibitors with carboxylic acid bioisosteres at the P-4 and P-1' positions. In the current study, we screened new P-1' position 1-phenylcycloalkylamine analogs to find non-acidic inhibitors that possess double-digit nanomolar range IC50 values. An extensive structure-activity relationship study was performed with various amine derivatives at the P-1' position. The most potent inhibitor of this pentapeptide series, KMI-1830, possessing 1-phenylcyclopentylamine at the P-1' position had an IC50 value of 11.6 nM against BACE1 in vitro enzymatic assay. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.07.002

文献信息

• Structure-guided design and synthesis of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.gif" overflow="scroll"><mml:mrow><mml:mmultiscripts><mml:mrow><mml:mtext>P</mml:mtext></mml:mrow><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:none /><mml:none /><mml:mrow><mml:mo>′</mml:mo></mml:mrow></mml:mmultiscripts></mml:mrow></mml:math> position 1-phenylcycloalkylamine-derived pentapeptidic BACE1 inhibitors
  作者：Harichandra D. Tagad、Yoshio Hamada、Jeffrey-Tri Nguyen、Koushi Hidaka、Takashi Hamada、Youhei Sohma、Tooru Kimura、Yoshiaki Kiso

  DOI：10.1016/j.bmc.2011.07.002

  日期：2011.9

  Previously, we reported potent pentapeptidic BACE1 inhibitors with the hydroxymethylcarbonyl isostere as a substrate transition-state mimic. To improve the in vitro potency, we further reported pentapeptidic inhibitors with carboxylic acid bioisosteres at the P-4 and P-1' positions. In the current study, we screened new P-1' position 1-phenylcycloalkylamine analogs to find non-acidic inhibitors that possess double-digit nanomolar range IC50 values. An extensive structure-activity relationship study was performed with various amine derivatives at the P-1' position. The most potent inhibitor of this pentapeptide series, KMI-1830, possessing 1-phenylcyclopentylamine at the P-1' position had an IC50 value of 11.6 nM against BACE1 in vitro enzymatic assay. (C) 2011 Elsevier Ltd. All rights reserved.