The effect of dihydronicotinate N-substitution on the brain-targeting efficacy of a zidovudine chemical delivery system

Enhanced brain delivery of zidovudine (AZT) has been demonstrated using a redox-based chemical delivery system (CDS). Optimization of the prototype AZT-CDS (5'-[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]-3'-azido-3'-deoxy thymidine ) was investigated by manipulation of the N-methyl g...

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Bibliographic Details
Published in:Pharmaceutical research 1993-09, Vol.10 (9), p.1356-1362
Main Authors: BREWSTER, M. E, POP, E, BRAUNSTEIN, A. J, POP, A. C, DRUZGALA, P, DINCULESCU, A, ANDERSON, W, ELKOUSSI, A, BODOR, N
Format: Article
Language:English
Subjects:
AIDS/HIV
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Biological and medical sciences
Blood-Brain Barrier
Brain - drug effects
Brain - metabolism
Chemical Phenomena
Chemistry, Physical
Chromatography, High Pressure Liquid
Dihydropyridines - chemical synthesis
Dihydropyridines - pharmacokinetics
Half-Life
In Vitro Techniques
Injections, Intravenous
Male
Medical sciences
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Tissue Distribution
Zidovudine - administration & dosage
Zidovudine - analogs & derivatives
Zidovudine - chemical synthesis
Zidovudine - pharmacokinetics
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Summary:Enhanced brain delivery of zidovudine (AZT) has been demonstrated using a redox-based chemical delivery system (CDS). Optimization of the prototype AZT-CDS (5'-[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]-3'-azido-3'-deoxy thymidine ) was investigated by manipulation of the N-methyl group present on the dihydronicotinate portion of the molecule and examining the release of AZT in vivo in a rat model. Of the five compounds examined, all produced higher brain levels and lower blood levels of AZT than did AZT itself. In comparing the novel AZT-CDS analogues to the N-methyl benchmark, the N-propyl system proved to be the most efficient of the compounds tested.
ISSN:0724-8741
1573-904X
DOI:10.1023/A:1018986217181