N-tert-butoxycarbonyl-L-prolyl-L-phenylalanylpamidronate

• 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: N-tert-butoxycarbonyl-L-prolyl-L-phenylalanylpamidronate
• 英文别名: [1-hydroxy-3-[[(2S)-2-[[(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]-1-phosphonopropyl]phosphonic acid
• 化学式: C₂₂H₃₅N₃O₁₁P₂
• 分子量: 579.481
• InChiKey: LCVLFKINQZVACN-IRXDYDNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.6
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  223
• 氢给体数：
  7
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  1-[叔丁氧羰基]-L-脯氨酰-L-苯丙氨酸 在 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 94.0h， 生成 N-tert-butoxycarbonyl-L-prolyl-L-phenylalanylpamidronate
  参考文献：
  名称：

  A Peptide Prodrug Approach for Improving Bisphosphonate Oral Absorption

  摘要：

  This work was aimed at improving the absorption of bisphosphonates by targeting carrier systems in the intestine and the intestinal peptide carrier system (hPEPT1), in particular. C-14-Labeled pamidronate and alendronate as well as radiolabeled and "cold" peptidyl-bisphosphonates, Pro-[H-3]Phe-[C-14]pamidronate, and Pro-[H-3]Phe-[C-14]alendronate were synthesized. In situ single-pass perfusion studies revealed competitive inhibition of transport by Pro-Phe, suggesting peptide carrier-mediated transport. Prodrug transport in the Caco-2 cell line was significantly better than that of the parent drugs, and the prodrugs exhibited high affinity to the intestinal tissue. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration in rats, and the bioavailability of Pro-Phe-alendronate was 3.3 (F-TIBIA) and 1.9 (F-URINE) times higher than that of the parent drug. The results indicate that the oral absorption of bisphosphonates can be improved by peptidyl prodrugs via the hPEPT1; however, other transporters may also be involved.

  DOI：

  10.1021/jm980645y

文献信息

• A Peptide Prodrug Approach for Improving Bisphosphonate Oral Absorption
  作者：Aviva Ezra、Amnon Hoffman、Eli Breuer、Ivan S. Alferiev、Jukka Mönkkönen、Naama El Hanany-Rozen、Gal Weiss、David Stepensky、Irith Gati、Hagit Cohen、Soili Törmälehto、Gordon L. Amidon、Gershon Golomb

  DOI：10.1021/jm980645y

  日期：2000.10.1

  This work was aimed at improving the absorption of bisphosphonates by targeting carrier systems in the intestine and the intestinal peptide carrier system (hPEPT1), in particular. C-14-Labeled pamidronate and alendronate as well as radiolabeled and "cold" peptidyl-bisphosphonates, Pro-[H-3]Phe-[C-14]pamidronate, and Pro-[H-3]Phe-[C-14]alendronate were synthesized. In situ single-pass perfusion studies revealed competitive inhibition of transport by Pro-Phe, suggesting peptide carrier-mediated transport. Prodrug transport in the Caco-2 cell line was significantly better than that of the parent drugs, and the prodrugs exhibited high affinity to the intestinal tissue. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration in rats, and the bioavailability of Pro-Phe-alendronate was 3.3 (F-TIBIA) and 1.9 (F-URINE) times higher than that of the parent drug. The results indicate that the oral absorption of bisphosphonates can be improved by peptidyl prodrugs via the hPEPT1; however, other transporters may also be involved.