| Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir. | |
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MedLine Citation:
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PMID: 17161946 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cidofovir (HPMPC) is a broad-spectrum anti-viral agent whose potential, particularly in biodefense scenarios, is limited by its low oral bioavailability. Two prodrugs (3 and 4) created by conjugating ethylene glycol-linked amino acids (L-Val, L-Phe) with the cyclic form of cidofovir (cHPMPC) via a P-O ester bond were synthesized and their pH-dependent stability (3 and 4), potential for in vivo reconversion to drug (3), and oral bioavailability (3) were evaluated. The prodrugs were stable in buffer between pH 3 and 5, but underwent rapid hydrolysis in liver (t(1/2) = 3.7 min), intestinal (t(1/2) = 12.5 min), and Caco-2 cell homogenates (t(1/2) = 20.2 min). In vivo (rat), prodrug 3 was >90% reconverted to cHPMPC. The prodrug was 4x more active than ganciclovir (IC50 value, 0.68 microM vs 3.0 microM) in a HCMV plaque reduction assay. However, its oral bioavailability in a rat model was similar to the parent drug. The contrast between the promising activation properties and unenhanced transport of the prodrug is briefly discussed. |
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Authors:
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Ulrika Eriksson; John M Hilfinger; Jae-Seung Kim; Stefanie Mitchell; Paul Kijek; Katherine Z Borysko; Julie M Breitenbach; John C Drach; Boris A Kashemirov; Charles E McKenna |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2006-11-10 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 17 ISSN: 0960-894X ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-01-22 Completed Date: 2007-04-03 Revised Date: 2011-05-05 |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 583-6 Citation Subset: IM |
Affiliation:
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Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, 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* Animals Antiviral Agents / chemical synthesis*, metabolism*, pharmacokinetics Biological Availability Biotransformation Cell Survival / drug effects Cytosine / analogs & derivatives*, chemical synthesis, metabolism, pharmacokinetics Ethylene Glycol / chemistry* Half-Life Humans Hydrolysis KB Cells Magnetic Resonance Spectroscopy Phenylalanine / chemistry Phosphonic Acids / chemical synthesis*, metabolism*, pharmacokinetics Plaque Assay Prodrugs / chemical synthesis*, metabolism* Rats Symporters / metabolism Valine / chemistry |
| Grant Support | |
ID/Acronym/Agency:
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R43 AI056864/AI/NIAID NIH HHS; R43 AI056864-01/AI/NIAID NIH HHS; R43 AI056864-02/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids; 0/Antiviral Agents; 0/PepT1 protein; 0/Phosphonic Acids; 0/Prodrugs; 0/Symporters; 107-21-1/Ethylene Glycol; 113852-37-2/cidofovir; 63-91-2/Phenylalanine; 7004-03-7/Valine; 71-30-7/Cytosine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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