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 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.
Brewster
M E
ME
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville 32610.
Pop
E
E
Braunstein
A J
AJ
Pop
A C
AC
Druzgala
P
P
Dinculescu
A
A
Anderson
W
W
Elkoussi
A
A
Bodor
N
N
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D015215:Zidovudine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics
D004095:Dihydropyridines; C056534:5'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-3'-azido-3'-deoxythymidine; D015215:Zidovudine