In vivo biodistribution, pharmacokinetic parameters, and brain uptake of 5-halo-y-methoxy(or ethoxy)-5,6-dihydro-3'-azido-3'-deoxythymidine diastereomers as potential prodrugs of 3'-azido-3'-deoxythymidine.

Abstract

A new class of 5-halo-6-alkoxy-5,6-dihydro-3'-azido-3'-deoxythymidine diastereomers (5-x-6-OR -5,6-dihydro-AZTs; X = I, Br, Cl; R = Me, Et) were evaluated as potential anti-AIDS prodrugs of 3'-azido-3'-deoxythimidine (AZT). In vivo regeneration of AZT from these 5-X-6-OR-5,6-dihydro-AZTs was examined in Balb/c mice after intravenous tail vein injection. The (5R,6R)- and (5S,6S)-5-bromo(or iodo)-6-methoxy-5,6-dihydro derivatives of AZT (BMAZT, IMAZT) were rapidly converted to AZT, resulting in AZT plasma concentrations after a 144 micromol/kg dose similar to those after an equivalent dose (144 microg/kg, 38.5 mg/kg) of AZT, whereas AZT was not detectable by HPLC after the same dose of the chloro diastereomer (5R,6R)-CMAZT. The interaction of AZT and the 5-X-6-methoxy-5,6dihydro-AZT diastereomers with the 6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine equilibrative-sensitive nucleoside transporter in murine erythrocytes was also studied. The (5R,6R)- and (5S,6S)-5-X-6-OMe-5,6-dihydro-AZT diastereomers demonstrated a high affinity (K(i) = 0.2-0.5 mM) for the transporter relative to AZT (K(i) = 1.3 mM), with the exception of (5S,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (CMAZT) which has a K(i) value larger than 1.5 mM. [2-(14)C]-Labeled (5R,6R)- and (5S,6S)-5-bromo-6-methoxy(or ethoxy)- 5,6-dihydro-3'-azido-3'-deoxythymidines were synthesized by the regiospecific addition of methyl hypobromite or ethyl hypobromite to the 5,6-olefinic bond of [2-(14)C]-AZT in high radiochemical yield [(5R,6R)-BMAZT, 48%, and (5S,6S)-BMAZT, 33%; (5R,6R)-BEAZT, 61%, and (5S,6S)-BEAZT, 15%), high radiochemical purity (>98%), and high specific activity (56mCi/mmol)]. The amounts of radioactivity in mouse brain after iv injection of [2-(14))C]-labeled (5R,6R)-BMAZT, (5S,6S)-BMAZT, or (5R,6R)-BEAZT were 2-4 fold higher that that for [2-(14)C]-AZT (P < 0.05). The radioactivity remaining in blood after dosing with these 5-bromo-6-alkoxy-5,6-dihydro-AZTs was up to 20-fold higher than after injection of [2-(14)C]-AZT at longer time intervals after injection. The amounts of radioactivity present in femoral bone following injection of [2(-14)C]-AZT, or these 5-bromo-6-alkoxy-5,6-dihydro-AZTs, were similar. Subcellular and regional distributions of [2-(14)C]-labeled AZT, (5R,6R)-BMAZT, or (5R,6R)-BEAZT in mouse brain after jugular vein injection did not show preferential concentration in any particular subcellular fraction nor a marked preferential regional localization for either AZT or these 5,6-dihydro prodrugs of AZT.

• Authors: L Wang, K W Morin, R Kumar, M Cheraghali, K G Todd, G B Baker, E E Knaus, L I Wiebe
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 39 Issue 4 Pg. 826-33 (Feb 16 1996) ISSN: 0022-2623 [Print] United States
• PMID: 8632406 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Carbon Radioisotopes
• Dideoxynucleosides
• Indicators and Reagents
• Prodrugs
• Zidovudine

Topics

• Acquired Immunodeficiency Syndrome (drug therapy)
• Animals
• Antiviral Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Bone and Bones (metabolism)
• Brain (metabolism)
• Carbon Radioisotopes
• Dideoxynucleosides (chemical synthesis, pharmacokinetics, pharmacology)
• Erythrocytes (drug effects, metabolism)
• Humans
• Indicators and Reagents
• Mice
• Mice, Inbred BALB C
• Prodrugs (chemical synthesis, pharmacokinetics, pharmacology)
• Radioisotope Dilution Technique
• Stereoisomerism
• Structure-Activity Relationship
• Tissue Distribution
• Zidovudine (analogs & derivatives, pharmacokinetics)