A pro-drug of zidovudine with enhanced efficacy against human immunodeficiency virus

In an attempt to alleviate the drug-related toxicity of zidovudine in patients with AIDS, a pro-drug of zidovudine, 5'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3'-azido-2',3'- dideoxythymidine (DP-AZT), has been evaluated. Cellular uptake by H9 cells and peripheral blood lymphocytes (PBL) with zidovudine and DP-AZT showed at least a 50% greater intracellular concentration of DP-AZT within 2 hr. DP-AZT was significantly less toxic to murine bone marrow cells as measured by CFU-E assay. The ED50 concentration to inhibit the production of HIV specific p24 antigen was 0.05 microM for DP-AZT whereas zidovudine required 0.125 microM. These results demonstrated that DP-AZT has a higher therapeutic ratio than zidovudine as an anti-HIV-1 agent.