N-(tert-butyloxycarbonyl)-Nπ-imid-<(benzyloxy)methyl>-L-phenylalanylglycyl-L-histidyl-4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-alanyl-L-phenylalanine methyl ester | 112151-87-8

• 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-(tert-butyloxycarbonyl)-Nπ-imid-<(benzyloxy)methyl>-L-phenylalanylglycyl-L-histidyl-4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-alanyl-L-phenylalanine methyl ester
• 英文别名: N-(tert-butyloxycarbonyl)-N^ϖ-imid-<(benzyloxy)methyl>-L-phenylalanylglycyl-L-histidyl-4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-alanyl-L-phenylalanine methyl ester；N-(tert-butyloxycarbonyl)-N^ϖ-imid-[(benzyloxy)methyl]-L-phenylalanylglycyl-L-histidyl-4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-alanyl-L-phenylalanine methyl ester
• CAS: 112151-87-8
• 化学式: C₅₁H₆₈N₈O₁₁
• 分子量: 969.148
• InChiKey: MCXNHRFMHYKBFQ-YBPCYDHQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.02
• 重原子数：
  70.0
• 可旋转键数：
  26.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  257.41
• 氢给体数：
  7.0
• 氢受体数：
  13.0

反应信息

• 作为反应物：
  描述：

  N-(tert-butyloxycarbonyl)-Nπ-imid-<(benzyloxy)methyl>-L-phenylalanylglycyl-L-histidyl-4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-alanyl-L-phenylalanine methyl ester 在 palladium on activated charcoal 氢气 作用下， 以 水 、 溶剂黄146 为溶剂， 反应 12.0h， 以69%的产率得到methyl (2S)-2-[[(2S)-2-[[(3S,4S)-3-hydroxy-4-[[(2S)-3-(1H-imidazol-5-yl)-2-[[2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]acetyl]amino]propanoyl]amino]-6-methylheptanoyl]amino]propanoyl]amino]-3-phenylpropanoate
  参考文献：
  名称：

  Inhibition of porcine pepsin by two substrate analogs containing statine. The effect of histidine at the P2 subsite on the inhibition of aspartic proteinases

  摘要：

  Two new inhibitors, 4 and 5, of the aspartic proteinase porcine pepsin were synthesized. These compounds, which span the P4-P'3 binding subsites of the enzyme, were derived by replacing the Nph-Phe dipeptidyl unit of a good pepsin substrate, H2N-Phe-Gly-His-Nph-Phe-Ala-Phe-OMe (3), with statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, Sta]. Hexapeptide 5, H2N-Phe-Gly-Val-(S,S)-Sta-Ala-Phe-OMe, is an extremely potent inhibitor of pepsin with a Ki value less than 1 nM. This result is consistent with the proposal that statine functions as a bioisosteric replacement for a substrate dipeptidyl unit. Compound 4, which contains His at P2, is 2 orders of magnitude less active than the valine analogue 5 (Ki = 150 nM). The factor for the decrease in binding to pepsin effected by replacement of Val by His at P2 parallels the ratio of protonated vs unprotonated imidazole group in peptide 4 at pH 4, according to the Henderson-Hasselbach equation. This result suggests that a positively charged side chain at P2 is undesirable for maximum pepsin inhibition. Kinetic constants for several known inhibitors of pepsin and renin are presented that demonstrate that the effect of His incorporation at P2 on pepsin inhibition depends upon the peptide sequence and that the effect is considerably different for renin inhibitors. We further suggest that the high selectivity of potent renin inhibitors known to be only weak pepsin and cathepsin D inhibitors is due in part to the extent of histidine protonation at P2 arising from pH differences in the inhibition kinetics assay of renin (neutral conditions) compared to other aspartic proteinases (acid pH 2-4).

  DOI：

  10.1021/jm00398a022
• 作为产物：
  描述：

  N-(tert-butyloxycarbonyl)-Nπ-imid-(benzyloxymethyl)-L-hystidyl-4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid ethyl ester 在 盐酸 、 sodium hydroxide 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 N-(tert-butyloxycarbonyl)-Nπ-imid-<(benzyloxy)methyl>-L-phenylalanylglycyl-L-histidyl-4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-alanyl-L-phenylalanine methyl ester
  参考文献：
  名称：

  Inhibition of porcine pepsin by two substrate analogs containing statine. The effect of histidine at the P2 subsite on the inhibition of aspartic proteinases

  摘要：

  Two new inhibitors, 4 and 5, of the aspartic proteinase porcine pepsin were synthesized. These compounds, which span the P4-P'3 binding subsites of the enzyme, were derived by replacing the Nph-Phe dipeptidyl unit of a good pepsin substrate, H2N-Phe-Gly-His-Nph-Phe-Ala-Phe-OMe (3), with statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, Sta]. Hexapeptide 5, H2N-Phe-Gly-Val-(S,S)-Sta-Ala-Phe-OMe, is an extremely potent inhibitor of pepsin with a Ki value less than 1 nM. This result is consistent with the proposal that statine functions as a bioisosteric replacement for a substrate dipeptidyl unit. Compound 4, which contains His at P2, is 2 orders of magnitude less active than the valine analogue 5 (Ki = 150 nM). The factor for the decrease in binding to pepsin effected by replacement of Val by His at P2 parallels the ratio of protonated vs unprotonated imidazole group in peptide 4 at pH 4, according to the Henderson-Hasselbach equation. This result suggests that a positively charged side chain at P2 is undesirable for maximum pepsin inhibition. Kinetic constants for several known inhibitors of pepsin and renin are presented that demonstrate that the effect of His incorporation at P2 on pepsin inhibition depends upon the peptide sequence and that the effect is considerably different for renin inhibitors. We further suggest that the high selectivity of potent renin inhibitors known to be only weak pepsin and cathepsin D inhibitors is due in part to the extent of histidine protonation at P2 arising from pH differences in the inhibition kinetics assay of renin (neutral conditions) compared to other aspartic proteinases (acid pH 2-4).

  DOI：

  10.1021/jm00398a022