N1-[(2S,3R)-3-hydroxy-4-(5-(methylthio)-1,3,4-thiadiazol-2-ylamino)-4-oxo-1-phenylbutan-2-yl]-5-(N-methylmethanesulfonamido)-N3-[(R)-1-phenylethyl]isophthalamide

• 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: N1-[(2S,3R)-3-hydroxy-4-(5-(methylthio)-1,3,4-thiadiazol-2-ylamino)-4-oxo-1-phenylbutan-2-yl]-5-(N-methylmethanesulfonamido)-N3-[(R)-1-phenylethyl]isophthalamide
• 英文别名: KMI-1746；3-N-[(2S,3R)-3-hydroxy-4-[(5-methylsulfanyl-1,3,4-thiadiazol-2-yl)amino]-4-oxo-1-phenylbutan-2-yl]-5-[methyl(methylsulfonyl)amino]-1-N-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide
• 化学式: C₃₁H₃₄N₆O₆S₃
• 分子量: 682.846
• InChiKey: AKORZIPGEMIDOQ-JSRBVGTNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  46
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  233
• 氢给体数：
  4
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  (2R,3S)-N-(tert-butoxycarbonyl)-3-amino-2-hydroxy-4-phenylbutanoic acid methyl ester 在 盐酸 、 水 、 1-羟基苯并三唑 、 苯甲醚 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.75h， 生成 N1-[(2S,3R)-3-hydroxy-4-(5-(methylthio)-1,3,4-thiadiazol-2-ylamino)-4-oxo-1-phenylbutan-2-yl]-5-(N-methylmethanesulfonamido)-N3-[(R)-1-phenylethyl]isophthalamide
  参考文献：
  名称：

  Novel BACE1 inhibitors with a non-acidic heterocycle at the P1′ position

  摘要：

  We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P-1' position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P-1' position. KMI-1764 (27) exhibited potent inhibitory activity (IC50 = 27 nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure-activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.08.016

文献信息

• Novel BACE1 inhibitors with a non-acidic heterocycle at the P1′ position
  作者：Kenji Suzuki、Yoshio Hamada、Jeffrey-Tri Nguyen、Yoshiaki Kiso

  DOI：10.1016/j.bmc.2013.08.016

  日期：2013.11

  We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P-1' position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P-1' position. KMI-1764 (27) exhibited potent inhibitory activity (IC50 = 27 nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure-activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model. (C) 2013 Elsevier Ltd. All rights reserved.