Antiretroviral activity, biochemistry, and pharmacokinetics of 3'-azido-2',3'-dideoxy-5-methylcytidine.
3'-Azido-2',3'-dideoxy-5-methylcytidine (CS-92, AzddMeC) is an antiviral nucleoside analogue structurally related to 3'-azido-3'-deoxythymidine (AZT). CS-92 is a potent and selective inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in human lymphocytes and macrophages. The EC50 for CS-92 in HIV-1-infected human PBM cells was 0.09 microM. In HIV-1-infected human macrophages, the EC50 was 0.006 microM. This compound was also effective against human immunodeficiency virus type 2 in lymphocytes. The replication of Friend murine virus was only weakly inhibited, and no effect was observed against herpes simplex virus type 1 and type 2 and coxsackievirus B4. CS-92 was not toxic to PBM or Vero cells when tested up to 200 microM and was, furthermore, at least 40 times less toxic to granulocyte-macrophage and erythroid precursor cells in vitro than was AZT. The interaction of the 5'-triphosphate of CS-92 with HIV-1 reverse transcriptase indicated competitive inhibition (the inhibition constant, Kis, was 0.0093 microM) with a 30-fold greater affinity for CS-92-TP than for ddCTP. CS-92-TP inhibited HIV-1 reverse transcriptase by 50% at a concentration 6,000-fold lower than that which was required for a similar inhibition of DNA polymerase alpha. Pharmacokinetic studies showed that CS-92 was not deaminated to AZT in rats, but this compound was found to have a half-life of 2.7 hours. In rhesus monkeys, however, a compound with a retention time and ultraviolet spectra characteristics similar to AZT was detected. The mean half-life in rhesus monkeys for CS-92 was 1.52 and 1.74 h after intravenous and oral administration, respectively, and the oral bioavailability was about 21 percent. Additional preclinical studies with CS-92 will determine the ultimate utility of this antiviral agent for the treatment of HIV-1 infections.
Schinazi
R F
RF
Veterans Affairs Medical Center, Decatur, Georgia 30033.
Chu
C K
CK
Eriksson
B F
BF
Sommadossi
J P
JP
Doshi
K J
KJ
Boudinot
F D
FD
Oswald
B
B
McClure
H M
HM
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001386:Azides / Q000494:pharmacology*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D051381:Rats; D016047:Zalcitabine / Q000031:analogs & derivatives*
D000998:Antiviral Agents; D001386:Azides; D015224:Dideoxynucleosides; D016047:Zalcitabine; C057658:3'-azido-2',3'-dideoxy-5-methylcytidine; D012194:RNA-Directed DNA Polymerase; D004259:DNA-Directed DNA Polymerase