%0 Journal Article %A Anastasia L. Khandazhinskaya %A Dmitry V. Yanvarev %A Maxim V. Jasko %A Alexander V. Shipitsin %A Vsevolod A. Khalizev %A Stanislav I. Shram %A Yuriy S. Skoblov %A Elena A. Shirokova %A Marina K. Kukhanova %T 5′-Aminocarbonyl Phosphonates as New Zidovudine Depot Forms: Antiviral Properties, Intracellular Transformations, and Pharmacokinetic Parameters %D 2009 %R 10.1124/dmd.108.022269 %J Drug Metabolism and Disposition %P 494-501 %V 37 %N 3 %X The main disadvantages of 3′-azido-3′-deoxythymidine (zidovudine, AZT), the most common anti-HIV drug, are toxicity and a short half-life in the organism. The introduction of an H-phosphonate group into the AZT 5′ position resulted in significant improvement of its therapeutic properties and allowed a new anti-HIV drug, Nikavir (AZT H-phosphonate). In this work, we described a new group of AZT derivatives, namely, AZT 5′-aminocarbonylphosphonates. The synthesized compounds displayed antiviral properties in cell cultures infected with HIV-1 and the capacity to release the active nucleoside in animals (rabbits and dogs) in a dose-dependent manner. The compounds were less toxic in MT-4 and HL-60 cell cultures and experimental animals compared with AZT. Major metabolites found in MT-4 cells after their incubation with AZT 5′-aminocarbonylphosphonate 1 were AZT and AZT 5′-phosphate (25 and 55%, respectively). Among the tested compounds, phosphonate 1 was the most effective AZT donor, and its longest t1/2 and Tmax values in the line phosphonate 1 - AZT H-phosphonate - AZT imply that compound 1 is an extended depot form of AZT. Although bioavailability of AZT after oral administration of phosphonate 1 was lower than those of AZT H-phosphonate and AZT (8 against 14 and 49%), we expect that this reduction would not cause essential decrease of antiviral activity but noticeably decrease toxicity as a result of gradual accumulation of AZT in blood and the absence of sharp difference between Cmax and Cmin. Such a combination of properties makes the compounds of this group promising for further studies as extended-release forms of AZT. The American Society for Pharmacology and Experimental Therapeutics %U https://dmd.aspetjournals.org/content/dmd/37/3/494.full.pdf