Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach.

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Sun J, Dahan A, Amidon GL

Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach.

J Med Chem. 2010 Jan 28;53(2):624-32. doi: 10.1021/jm9011559.

PubMed ID

19957998 [ View in PubMed

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Abstract

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 (IC(50): 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) x s(-1): Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, a prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogues via targeting hPEPT1 for transport and hVACVase for activation.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Valaciclovir	Solute carrier family 15 member 1	IC 50 (nM)	1420000	N/A	N/A	Details