Synthesis and Anti-HIV Properties of New Carbamate Prodrugs of AZT

Abstract

A series of new 5'-O-carbamate prodrugs of AZT have been prepared. The stability in biological media, anti-HIV properties and pharmacokinetic parameters in dogs were evaluated. The compounds display moderate anti-HIV activity in cell culture. After oral administration of carbamate IV in dogs, both intact prodrug IV and released AZT were discovered in dog blood. Pharmacokinetic parameters of the compound IV were estimated. Half-life (T1/2) of AZT released after oral administration of IV in dogs was close to that after administration of AZT itself, and time to the maximum concentration (Tmax) of AZT released from IV was two and three times longer compared with that of AZT and H-phosphonate AZT, respectively. Acute toxicity was more than five times less if compared with AZT. As a result, we consider this series of carbamate derivatives of AZT as perspective for development of anti-HIV agents. A series of new 5'-O-carbamate prodrugs of AZT have been prepared. The stability in biological media, anti-HIV properties and pharmocokinetic parameters in dogs were evaluated. © 2012 John Wiley & Sons A/S.