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

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

Jing Sun  1 , Arik Dahan, Gordon L Amidon
Affiliations

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

Jing Sun et al. J Med Chem. .

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.

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Figures

Figure 1
Figure 1
Apparent apical-to-basolateral permeability coefficient (Papp) across Caco-2 monolayers (mean ± SEM; n=3; *difference is statistically significant).
Figure 2
Figure 2
Apparent apical-to-basolateral permeability coefficient (Papp) of Val-3-HPG without or with 5 mM inhibitors across Caco-2 monolayers. (mean ± SEM; n=3; * difference is statistically significant).
Figure 3
Figure 3
Rat jejunal membrane permeability (mean ± SEM; metoprolol, n=12; others, n=4; *difference is statistically significant).
Scheme 1
Scheme 1
Structures of guanidino-containing drugs zanamivir and argatroban.
Scheme 2
Scheme 2
Structures of 3-HPG and its L-valine, L-isoleucine, L-phenylalanine and D-valine esters.
Scheme 3
Scheme 3
Synthesis of 3-HPG and its valine, isoleucine, phenylalanine and D-valine esters.
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