tert-butyl (8S)-9-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-cyclohexyloxy-1,4-dioxobutan-2-yl]amino]-8-[[(2R)-3-(1H-indol-3-yl)-2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-9-oxononanoate | 187396-04-9

• 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: tert-butyl (8S)-9-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-cyclohexyloxy-1,4-dioxobutan-2-yl]amino]-8-[[(2R)-3-(1H-indol-3-yl)-2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-9-oxononanoate
• CAS: 187396-04-9
• 化学式: C₄₉H₇₀N₆O₁₀
• 分子量: 903.129
• InChiKey: LUIJARQLFQDBQM-CNDFGUIESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  65
• 可旋转键数：
  27
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  237
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  tert-butyl (8S)-9-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-cyclohexyloxy-1,4-dioxobutan-2-yl]amino]-8-[[(2R)-3-(1H-indol-3-yl)-2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-9-oxononanoate 在 氢氟酸 、 碳酸氢钠 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 苯甲醚 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.75h， 生成 (3S)-4-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-3-[[(2R,5S)-2-(1H-indol-3-ylmethyl)-2-methyl-3,12-dioxo-1,4-diazacyclododecane-5-carbonyl]amino]-4-oxobutanoic acid
  参考文献：
  名称：

  Structure-Based Design of New Constrained Cyclic Agonists of the Cholecystokinin CCK-B Receptor

  摘要：

  New constrained cyclic pseudopeptide cholecystokinin-B (CCK-B) agonists have been designed on the basis of conformational characteristics of the potent and selective CCK-B agonist Boc-Trp-(NMe)Nle-Asp-Phe-NH2 (K-i = 0.8 nm, selectivity ratio CCK-A/CCK-B > 6000) (Goudreau et al. Biopolymers, 1994, 34, 155-169). These compounds are among the first successful examples of macrocyclic constrained CCK4 analogs endowed with agonist properties and as such may be of value for the development of nonpeptide CCK-B agonists. The affinities and selectivities of these compounds for CCK-B and CCK-A receptors have been determined in vitro by measuring the displacement of [H-3]pCCK(8) binding to guinea pig cortex and pancreas membranes, respectively. The most potent compound, 8b, N-(cycloamido)-alpha-Me(R)Trp-[(2S)-2-amino-9-((cycloamido)carbonyl)nonanoyl]-Asp-Phe-NH2, has a K-i value of 15 +/- 1 nM for guinea pig cortex membranes with a good CCK-B selectivity ratio (CCK-A/CCK-B = 147). Furthermore, 8b behaved as a potent and full agonist in a functional assay which measures the stimulation of inositol phosphate accumulation in CHO cells transfected with the rat CCK-B receptor (EC(50) = 7 nM). The in vivo affinity of 8b for mouse brain CCK-B receptors was determined following intracerebroventricular injection (ID50 similar to 29 nmol/kg). 8b was also shown to cross the blood-brain barrier (0.16%), after intravenous administration in mice. 8b also increased gastric acid secretion measured in anesthetized rats after intravenous injection. Therefore, 8b appears to be an interesting pharmacological tool and is currently under investigation as a lead for further development of nonpeptide CCK-B agonists.

  DOI：

  10.1021/jm9603072
• 作为产物：
  描述：

  tert-butyl 7-bromoheptanoate 在 palladium on activated charcoal 六甲基磷酰三胺 、 lithium hydroxide 、 正丁基锂 、 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 、 柠檬酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 72.0h， 生成 tert-butyl (8S)-9-[[(2S)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-4-cyclohexyloxy-1,4-dioxobutan-2-yl]amino]-8-[[(2R)-3-(1H-indol-3-yl)-2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-9-oxononanoate
  参考文献：
  名称：

  Structure-Based Design of New Constrained Cyclic Agonists of the Cholecystokinin CCK-B Receptor

  摘要：

  New constrained cyclic pseudopeptide cholecystokinin-B (CCK-B) agonists have been designed on the basis of conformational characteristics of the potent and selective CCK-B agonist Boc-Trp-(NMe)Nle-Asp-Phe-NH2 (K-i = 0.8 nm, selectivity ratio CCK-A/CCK-B > 6000) (Goudreau et al. Biopolymers, 1994, 34, 155-169). These compounds are among the first successful examples of macrocyclic constrained CCK4 analogs endowed with agonist properties and as such may be of value for the development of nonpeptide CCK-B agonists. The affinities and selectivities of these compounds for CCK-B and CCK-A receptors have been determined in vitro by measuring the displacement of [H-3]pCCK(8) binding to guinea pig cortex and pancreas membranes, respectively. The most potent compound, 8b, N-(cycloamido)-alpha-Me(R)Trp-[(2S)-2-amino-9-((cycloamido)carbonyl)nonanoyl]-Asp-Phe-NH2, has a K-i value of 15 +/- 1 nM for guinea pig cortex membranes with a good CCK-B selectivity ratio (CCK-A/CCK-B = 147). Furthermore, 8b behaved as a potent and full agonist in a functional assay which measures the stimulation of inositol phosphate accumulation in CHO cells transfected with the rat CCK-B receptor (EC(50) = 7 nM). The in vivo affinity of 8b for mouse brain CCK-B receptors was determined following intracerebroventricular injection (ID50 similar to 29 nmol/kg). 8b was also shown to cross the blood-brain barrier (0.16%), after intravenous administration in mice. 8b also increased gastric acid secretion measured in anesthetized rats after intravenous injection. Therefore, 8b appears to be an interesting pharmacological tool and is currently under investigation as a lead for further development of nonpeptide CCK-B agonists.

  DOI：

  10.1021/jm9603072