(S)-2-[(5-{[3-(2-Methyl-benzyl)-3H-imidazol-4-ylmethyl]-amino}-biphenyl-2-carbonyl)-amino]-4-methylsulfanyl-butyric acid | 655235-53-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-[(5-{[3-(2-Methyl-benzyl)-3H-imidazol-4-ylmethyl]-amino}-biphenyl-2-carbonyl)-amino]-4-methylsulfanyl-butyric acid
• 英文别名: N-[[5-[[[1-[(2-Methylphenyl)methyl]-1H-imidazol-5-yl]methyl]amino][1,1a(2)-biphenyl]-2-yl]carbonyl]-L-methionine；(2S)-2-[[4-[[3-[(2-methylphenyl)methyl]imidazol-4-yl]methylamino]-2-phenylbenzoyl]amino]-4-methylsulfanylbutanoic acid
• CAS: 655235-53-3
• 化学式: C₃₀H₃₂N₄O₃S
• 分子量: 528.675
• InChiKey: ZTQZCCKWWMRVIS-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  122
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  methyl (2S)-2-[[4-[[3-[(2-methylphenyl)methyl]imidazol-4-yl]methylamino]-2-phenylbenzoyl]amino]-4-methylsulfanylbutanoate 在 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 以71%的产率得到(S)-2-[(5-{[3-(2-Methyl-benzyl)-3H-imidazol-4-ylmethyl]-amino}-biphenyl-2-carbonyl)-amino]-4-methylsulfanyl-butyric acid
  参考文献：
  名称：

  Design and Synthesis of Peptidomimetic Protein Farnesyltransferase Inhibitors as Anti-Trypanosoma brucei Agents

  摘要：

  On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucel protein farnesyltransferase (TbPFT) was evaluated. Peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nM in the enzyme assay, whereas the corresponding C-4 regioisomers were less potent. The ester prodrug 23 was found to be a potent inhibitor against cultured Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense cells with ED50 values of 0.025 and 0.0026 muM, respectively. Furthermore introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED50 of 0.0015 muM. The potency of the TbPFT inhibitors and the cytotoxicity of the corresponding esters to T. brucei cells were shown to be highly correlated. These studies validate TbPFT as a target for the development of novel therapeutics against African sleeping sickness.

  DOI：

  10.1021/jm030236o

文献信息

• Design and Synthesis of Peptidomimetic Protein Farnesyltransferase Inhibitors as Anti-<i>Trypanosoma brucei </i>Agents
  作者：Junko Ohkanda、Frederick S. Buckner、Jeffrey W. Lockman、Kohei Yokoyama、Dora Carrico、Richard Eastman、Kate de Luca-Fradley、Wendy Davies、Simon L. Croft、Wesley C. Van Voorhis、Michael H. Gelb、Saïd M. Sebti、Andrew D. Hamilton

  DOI：10.1021/jm030236o

  日期：2004.1.1

  On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucel protein farnesyltransferase (TbPFT) was evaluated. Peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nM in the enzyme assay, whereas the corresponding C-4 regioisomers were less potent. The ester prodrug 23 was found to be a potent inhibitor against cultured Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense cells with ED50 values of 0.025 and 0.0026 muM, respectively. Furthermore introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED50 of 0.0015 muM. The potency of the TbPFT inhibitors and the cytotoxicity of the corresponding esters to T. brucei cells were shown to be highly correlated. These studies validate TbPFT as a target for the development of novel therapeutics against African sleeping sickness.