{(S)-1-[(S)-1-((S)-3-Carbamoyl-1-formyl-propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester

• 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: {(S)-1-[(S)-1-((S)-3-Carbamoyl-1-formyl-propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester
• 英文别名: {1-[1-(3-Carbamoyl-1-formyl-propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester；benzyl N-[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1,5-dioxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate
• 化学式: C₂₈H₃₆N₄O₆
• 分子量: 524.617
• InChiKey: LUAUEQZREWTXGJ-HJOGWXRNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  38
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  157
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  磷酰基乙酸三乙酯 、 {(S)-1-[(S)-1-((S)-3-Carbamoyl-1-formyl-propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 1.0h， 生成 ethyl (4S)-7-amino-4-[[(2S)-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-phenylpropanoyl]amino]-7-oxohept-2-enoate
  参考文献：
  名称：

  Synthesis, activity and structure–activity relationship of noroviral protease inhibitors

  摘要：

  诺罗病毒（一种重要的人类病原体）的蛋白酶对其复制至关重要，因此是一个潜在的药物靶点。一系列基于三肽的蛋白酶抑制剂被设计、合成并测试，其中一些强效抑制剂被鉴定出来，其Ki值低至75 nM。这些抑制剂的结构-活性关系被讨论。

  DOI：

  10.1039/c3md00219e
• 作为产物：
  描述：

  苄氧羰基-亮氨酰-苯丙氨酸 在 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 2-碘酰基苯甲酸 作用下， 以 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 {(S)-1-[(S)-1-((S)-3-Carbamoyl-1-formyl-propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester
  参考文献：
  名称：

  Tripeptide Aldehyde Inhibitors of Human Rhinovirus 3C Protease:  Design, Synthesis, Biological Evaluation, and Cocrystal Structure Solution of P₁ Glutamine Isosteric Replacements

  摘要：

  The investigation of tripeptide aldehydes as reversible covalent inhibitors of human rhinovirus (HRV) 3C protease (3CP) is reported. Molecular models based on the apo crystal structure of HRV-14 3CP and other trypsin-like serine proteases were constructed to approximate the binding of peptide substrates, generate transition state models of P-1-P-1' amide cleavage, and propose novel tripeptide aldehydes. Glutaminal derivatives have limitations since they exist predominantly in the cyclic hemiaminal form. Therefore, several isosteric replacements for the P-1 carboxamide side chain were designed and incorporated into the tripeptide aldehydes. These compounds were found to be potent inhibitors of purified HRV-14 3CP with K(i)s ranging from 0.005 to 0.64 mu M. Several have low micromolar antiviral activity when tested against HRV-14-infected H1-HeLa cells. The N-acetyl derivative 3 was also shown to be active against HRV serotypes 2, 16, and 89. High-resolution cocrystal structures of HRV-8 3CP, covalently bound to compounds 3, 15, and 16, were solved. These cocrystal structures were analyzed and compared with our original HRV-14 3CP-substrate and inhibitor models.

  DOI：

  10.1021/jm980071x

文献信息

• Tripeptide Aldehyde Inhibitors of Human Rhinovirus 3C Protease:  Design, Synthesis, Biological Evaluation, and Cocrystal Structure Solution of P₁ Glutamine Isosteric Replacements
  作者：Stephen E. Webber、Koji Okano、Thomas L. Little、Siegfried H. Reich、Yue Xin、Shella A. Fuhrman、David A. Matthews、Robert A. Love、Thomas F. Hendrickson、Amy K. Patick、James W. Meador、Rose Ann Ferre、Edward L. Brown、Clifford E. Ford、Susan L. Binford、Stephen T. Worland

  DOI：10.1021/jm980071x

  日期：1998.7.1

  The investigation of tripeptide aldehydes as reversible covalent inhibitors of human rhinovirus (HRV) 3C protease (3CP) is reported. Molecular models based on the apo crystal structure of HRV-14 3CP and other trypsin-like serine proteases were constructed to approximate the binding of peptide substrates, generate transition state models of P-1-P-1' amide cleavage, and propose novel tripeptide aldehydes. Glutaminal derivatives have limitations since they exist predominantly in the cyclic hemiaminal form. Therefore, several isosteric replacements for the P-1 carboxamide side chain were designed and incorporated into the tripeptide aldehydes. These compounds were found to be potent inhibitors of purified HRV-14 3CP with K(i)s ranging from 0.005 to 0.64 mu M. Several have low micromolar antiviral activity when tested against HRV-14-infected H1-HeLa cells. The N-acetyl derivative 3 was also shown to be active against HRV serotypes 2, 16, and 89. High-resolution cocrystal structures of HRV-8 3CP, covalently bound to compounds 3, 15, and 16, were solved. These cocrystal structures were analyzed and compared with our original HRV-14 3CP-substrate and inhibitor models.
• Synthesis, activity and structure–activity relationship of noroviral protease inhibitors
  作者：Lisheng Deng、Zana Muhaxhiri、Mary K. Estes、Timothy Palzkill、B. V. Venkataram Prasad、Yongcheng Song

  DOI：10.1039/c3md00219e

  日期：——

  The protease of norovirus, an important human pathogen, is essential for the viral replication and, therefore, represents a potential drug target. A series of tripeptide-based inhibitors of the protease were designed, synthesized and tested, among which several potent inhibitors were identified with Ki values as low as 75 nM. The structure–activity relationships of these inhibitors are discussed.

  诺罗病毒（一种重要的人类病原体）的蛋白酶对其复制至关重要，因此是一个潜在的药物靶点。一系列基于三肽的蛋白酶抑制剂被设计、合成并测试，其中一些强效抑制剂被鉴定出来，其Ki值低至75 nM。这些抑制剂的结构-活性关系被讨论。