Document Detail


Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir.
MedLine Citation:
PMID:  17161946     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Related Documents :
3886546 - Succinic acid, a metabolic by-product of bacteroides species, inhibits polymorphonuclea...
8183636 - Intracellular ph regulation of human colonic crypt cells.
16154506 - Effect of hydraulic retention time on anaerobic hydrogenesis in cstr.
21042476 - Influence of organic acids on diltiazem hcl release kinetics from hydroxypropyl methyl ...
17345346 - Molluscicidal saponins of xeromphis spinosa.
2588936 - Pharmacokinetics of 3,5,3'-triiodothyroacetic acid and its effects on serum tsh levels.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-11-10
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  17     ISSN:  0960-894X     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-22     Completed Date:  2007-04-03     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  583-6     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amino Acids / 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
Organophosphonates / chemical synthesis*,  metabolism*,  pharmacokinetics
Phenylalanine / chemistry
Prodrugs / chemical synthesis*,  metabolism*
Rats
Symporters / metabolism
Valine / chemistry
Viral Plaque Assay
Grant Support
ID/Acronym/Agency:
R43 AI056864/AI/NIAID NIH HHS; R43 AI056864/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Antiviral Agents; 0/Organophosphonates; 0/PepT1 protein; 0/Prodrugs; 0/Symporters; 47E5O17Y3R/Phenylalanine; 8J337D1HZY/Cytosine; FC72KVT52F/Ethylene Glycol; HG18B9YRS7/Valine; JIL713Q00N/cidofovir
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  The crystal structure, self-assembly, DNA-binding and cleavage studies of the [2]pseudorotaxane comp...
Next Document:  Cell type-specific functions of Rho GTPases revealed by gene targeting in mice.