methyl (2S)-2-[[4-[[benzoyl(pyridin-3-yl)amino]methyl]-2-(2-methylphenyl)benzoyl]amino]-4-methylsulfanylbutanoate | 478908-22-4

• 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: methyl (2S)-2-[[4-[[benzoyl(pyridin-3-yl)amino]methyl]-2-(2-methylphenyl)benzoyl]amino]-4-methylsulfanylbutanoate
• CAS: 478908-22-4
• 化学式: C₃₃H₃₃N₃O₄S
• 分子量: 567.709
• InChiKey: GAAFOIWSTRBLKT-PMERELPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  41
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl (2S)-2-[[4-[[benzoyl(pyridin-3-yl)amino]methyl]-2-(2-methylphenyl)benzoyl]amino]-4-methylsulfanylbutanoate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 (S)-2-({5-[(Benzoyl-pyridin-3-yl-amino)-methyl]-2'-methyl-biphenyl-2-carbonyl}-amino)-4-methylsulfanyl-butyric acid
  参考文献：
  名称：

  Second-Generation Peptidomimetic Inhibitors of Protein Farnesyltransferase Demonstrating Improved Cellular Potency and Significant in Vivo Efficacy

  摘要：

  The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumorderived cell line.

  DOI：

  10.1021/jm9901935
• 作为产物：
  描述：

  N-(3-pyridinyl)benzamide 在 sodium hydroxide 、 sodium hydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 methyl (2S)-2-[[4-[[benzoyl(pyridin-3-yl)amino]methyl]-2-(2-methylphenyl)benzoyl]amino]-4-methylsulfanylbutanoate
  参考文献：
  名称：

  Second-Generation Peptidomimetic Inhibitors of Protein Farnesyltransferase Demonstrating Improved Cellular Potency and Significant in Vivo Efficacy

  摘要：

  The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumorderived cell line.

  DOI：

  10.1021/jm9901935

文献信息

• Second-Generation Peptidomimetic Inhibitors of Protein Farnesyltransferase Demonstrating Improved Cellular Potency and Significant in Vivo Efficacy
  作者：Stephen J. O'Connor、Kenneth J. Barr、Le Wang、Bryan K. Sorensen、Andrew S. Tasker、Hing Sham、Shi-Chung Ng、Jerome Cohen、Edward Devine、Sajeev Cherian、Badr Saeed、Haichao Zhang、Jang Yun Lee、Robert Warner、Stephen Tahir、Peter Kovar、Patricia Ewing、Jeffrey Alder、Michael Mitten、Juan Leal、Kennan Marsh、Joy Bauch、Daniel J. Hoffman、Said M. Sebti、Saul H. Rosenberg

  DOI：10.1021/jm9901935

  日期：1999.9.1

  The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumorderived cell line.