L-isoleucine [3-[(aminoiminomethyl)amino]phenyl]methyl ester | 1202641-34-6

• 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: L-isoleucine [3-[(aminoiminomethyl)amino]phenyl]methyl ester
• 英文别名: Ile-3-HPG；L-Isoleucine[3-[(Aminoiminomethyl)amino]phenyl]methyl Ester；[3-(diaminomethylideneamino)phenyl]methyl (2S,3S)-2-amino-3-methylpentanoate
• CAS: 1202641-34-6
• 化学式: C₁₄H₂₂N₄O₂
• 分子量: 278.354
• InChiKey: AKQJIOMDSJWVGR-CABZTGNLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  L-isoleucine [3-[(aminoiminomethyl)amino]phenyl]methyl ester 在 recombinant human valacyclovirase from Escherichia coli 作用下， 生成 L-异亮氨酸
  参考文献：
  名称：

  Enhancing the Intestinal Absorption of Molecules Containing the Polar Guanidino Functionality: A Double-Targeted Prodrug Approach

  摘要：

  A prodrug strategy was applied to guanidino-containing analogues to increase oral absorption via hPEPT1 and hVACVase. L-Valine, L-isoleucine, and L-phenylalanine esters of [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for transport and activation. In HeLa/hPEPT1 cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPT1 (IC50:0.65 and 0.63 mM, respectively), and all three L-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent Compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-HPG exhibited comparable permeability to valacyclovir. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG and exceeded/matched the high-permeability standard metoprolol, respectively. All the L-amino acid 3-HPG esters were effectively activated in HeLa and Caco-2 cell homogenates and were found to be good Substrates of hVACVase (k(cat)/K-m in mM(-1).s(-1): Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, it prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogues via targeting hPEPT1 for transport and hVACVase for activation.

  DOI：

  10.1021/jm9011559

文献信息

• Enhancing the Intestinal Absorption of Molecules Containing the Polar Guanidino Functionality: A Double-Targeted Prodrug Approach
  作者：Jing Sun、Arik Dahan、Gordon L. Amidon

  DOI：10.1021/jm9011559

  日期：2010.1.28

  A prodrug strategy was applied to guanidino-containing analogues to increase oral absorption via hPEPT1 and hVACVase. L-Valine, L-isoleucine, and L-phenylalanine esters of [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for transport and activation. In HeLa/hPEPT1 cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPT1 (IC50:0.65 and 0.63 mM, respectively), and all three L-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent Compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-HPG exhibited comparable permeability to valacyclovir. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG and exceeded/matched the high-permeability standard metoprolol, respectively. All the L-amino acid 3-HPG esters were effectively activated in HeLa and Caco-2 cell homogenates and were found to be good Substrates of hVACVase (k(cat)/K-m in mM(-1).s(-1): Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, it prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogues via targeting hPEPT1 for transport and hVACVase for activation.