| Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach. | |
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MedLine Citation:
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PMID: 19957998 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Jing Sun; Arik Dahan; Gordon L Amidon |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 53 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-01-21 Completed Date: 2010-03-02 Revised Date: 2012-03-19 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 624-32 Citation Subset: IM |
Affiliation:
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College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acids
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chemistry Antiviral Agents / chemical synthesis*, pharmacokinetics Caco-2 Cells Carboxylic Ester Hydrolases / metabolism Drug Delivery Systems / methods* Esters / chemistry Guanidines / chemical synthesis, pharmacokinetics* HeLa Cells Humans Intestinal Absorption* Kinetics Prodrugs / pharmacokinetics* Symporters / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM037188-23/GM/NIGMS NIH HHS; U01AI061457/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids; 0/Antiviral Agents; 0/Esters; 0/Guanidines; 0/Prodrugs; 0/SLC15A1 protein, human; 0/Symporters; 2002-16-6/phenylguanidine; EC 3.1.1.-/BPHL protein, human; EC 3.1.1.-/Carboxylic Ester Hydrolases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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