AOA-DADLE

• 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: AOA-DADLE
• 英文别名: (6S,9R,15S,18R)-15-benzyl-6-[(4-hydroxyphenyl)methyl]-9-methyl-18-(2-methylpropyl)-1,3-dioxa-5,8,11,14,17-pentazacyclononadecane-4,7,10,13,16,19-hexone
• 化学式: C₃₁H₃₉N₅O₉
• 分子量: 625.679
• InChiKey: CKUVQGMBYMBIHB-LJYZBVLISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  45
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  201
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  AOA-DADLE 在 rat liver homogenate 作用下， 以 水 、 二甲基亚砜 为溶剂， 反应 15.0h， 生成 聚合甲醛 、 二氧化碳 、 (D-丙2,D-亮5)-脑啡肽
  参考文献：
  名称：

  摘要：

  Purpose. To evaluate the chemical and enzymatic stability, as well as the cellular permeation characteristics, of the acyloxyalkoxy-based cyclic prodrugs (1) under bar and (2) under bar of the opioid peptides [Leu(5)]-enkephalin (H-Tyr-Cly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively.Methods. The rates of conversion of (1) under bar and (2) under bar to [Leu(5)]-enkephalin and DADLE, respectively, were measured by HPLC in HBSS, pH = 7.4, and in various biological media (e.g., human plasma and Caco-2 cell and rat liver homogenates) having measurable esterase activity. The cellular permeation and metabolism characteristics of [Leu(5)]-enkephalin, DADLE and the cyclic prodrugs (1) under bar and (2) under bar were measured using Caco-2 cell monolayers grown onto microporous membranes and monitored by HPLC.Results. Cyclic prodrugs (1) under bar and (2) under bar degraded slowly but stoichiometrically to [Leu(5)]-enkephalin and DADLE, respectively, in HBS, pH = 7.4. In homogenates of Caco-2 cells and rat liver, as well as 90% human plasma, the rates of disappearance of the cyclic prodrugs were significantly faster than in HBSS. The stabilities of the cyclic prodrugs (1) under bar and (2) under bar were increased significantly in 90% human plasma and Caco-2 cell homogenates when paraoxon, a potent inhibitor of serine-dependent esterases, was included in the incubation mixtures. A similar stabilizing effect of paraoxon was not observed in 50% rat liver homogenates, but was observed in 10% homogenates of rat liver. When applied to the AP side of a Caco-2 cell monolayer, DADLE and cyclic prodrugs (1) under bar and (2) under bar exhibited significantly greater stability than [Leu(5)]-enkephalin. Based on their physicochemical properties (i.e., lipophilicity), cyclic prodrugs (1) under bar and (2) under bar should have exhibited high permeation across Caco-2 cell monolayers. Surprisingly, the AP-to-BL apparent permeability coefficients (P-App) for cyclic prodrugs (1) under bar and (2) under bar across Caco-2 cell monolayers were significantly lower than the P-App value determined for the metabolically stable opioid peptide DADLE. When the P-App values for cyclic prodrugs (1) under bar and (2) under bar crossing Caco-2, cell monolayers in the BL-to-AP direction were determined, they were shown to be 36 and 52 times greater, respectively, than the AP-to-BL values.Conclusions. Cyclic prodrugs (1) under bar and (2) under bar prepared with an acyloxyalkoxy promoiety, were shown to degrade in biological media (e.g,, 90% human plasma) via an esterase-catalyzed pathway. The degradation of cyclic prodrug (1) under bar, which contained an ester formed with an L-amino acid, degraded more rapidly in esterase-containing media than did prodrug (2) under bar, which contained an ester formed with a D-amino acid. Cyclic prodrugs (1) under bar and (2) under bar showed very low AP-to-BL Caco-2 cell permeability, which did not correlate with their lipophilicities. These low AP-to-BL permeabilities result because of their substrate activity for apically polarized efflux systems.

  DOI：

  10.1023/a:1018854308829

文献信息

• ——
  作者：Annette Bak、Olafur S. Gudmundsson、Gitte J. Friis、Teruna J. Siahaan、Ronald T. Borchardt

  DOI：10.1023/a:1018854308829

  日期：——

  Purpose. To evaluate the chemical and enzymatic stability, as well as the cellular permeation characteristics, of the acyloxyalkoxy-based cyclic prodrugs (1) under bar and (2) under bar of the opioid peptides [Leu(5)]-enkephalin (H-Tyr-Cly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively.Methods. The rates of conversion of (1) under bar and (2) under bar to [Leu(5)]-enkephalin and DADLE, respectively, were measured by HPLC in HBSS, pH = 7.4, and in various biological media (e.g., human plasma and Caco-2 cell and rat liver homogenates) having measurable esterase activity. The cellular permeation and metabolism characteristics of [Leu(5)]-enkephalin, DADLE and the cyclic prodrugs (1) under bar and (2) under bar were measured using Caco-2 cell monolayers grown onto microporous membranes and monitored by HPLC.Results. Cyclic prodrugs (1) under bar and (2) under bar degraded slowly but stoichiometrically to [Leu(5)]-enkephalin and DADLE, respectively, in HBS, pH = 7.4. In homogenates of Caco-2 cells and rat liver, as well as 90% human plasma, the rates of disappearance of the cyclic prodrugs were significantly faster than in HBSS. The stabilities of the cyclic prodrugs (1) under bar and (2) under bar were increased significantly in 90% human plasma and Caco-2 cell homogenates when paraoxon, a potent inhibitor of serine-dependent esterases, was included in the incubation mixtures. A similar stabilizing effect of paraoxon was not observed in 50% rat liver homogenates, but was observed in 10% homogenates of rat liver. When applied to the AP side of a Caco-2 cell monolayer, DADLE and cyclic prodrugs (1) under bar and (2) under bar exhibited significantly greater stability than [Leu(5)]-enkephalin. Based on their physicochemical properties (i.e., lipophilicity), cyclic prodrugs (1) under bar and (2) under bar should have exhibited high permeation across Caco-2 cell monolayers. Surprisingly, the AP-to-BL apparent permeability coefficients (P-App) for cyclic prodrugs (1) under bar and (2) under bar across Caco-2 cell monolayers were significantly lower than the P-App value determined for the metabolically stable opioid peptide DADLE. When the P-App values for cyclic prodrugs (1) under bar and (2) under bar crossing Caco-2, cell monolayers in the BL-to-AP direction were determined, they were shown to be 36 and 52 times greater, respectively, than the AP-to-BL values.Conclusions. Cyclic prodrugs (1) under bar and (2) under bar prepared with an acyloxyalkoxy promoiety, were shown to degrade in biological media (e.g,, 90% human plasma) via an esterase-catalyzed pathway. The degradation of cyclic prodrug (1) under bar, which contained an ester formed with an L-amino acid, degraded more rapidly in esterase-containing media than did prodrug (2) under bar, which contained an ester formed with a D-amino acid. Cyclic prodrugs (1) under bar and (2) under bar showed very low AP-to-BL Caco-2 cell permeability, which did not correlate with their lipophilicities. These low AP-to-BL permeabilities result because of their substrate activity for apically polarized efflux systems.