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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.
R F Schinazi, and
C K Chu, and
B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
September 1998,
The Journal of pharmacy and pharmacology,
R F Schinazi, and
C K Chu, and
B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
January 1993,
Biochemical pharmacology,
R F Schinazi, and
C K Chu, and
B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
September 2013,
European journal of medicinal chemistry,
R F Schinazi, and
C K Chu, and
B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
April 1992,
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R F Schinazi, and
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B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
January 1994,
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R F Schinazi, and
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B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
August 1989,
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R F Schinazi, and
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B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
August 2004,
Antiviral research,
R F Schinazi, and
C K Chu, and
B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
July 1990,
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R F Schinazi, and
C K Chu, and
B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
April 1999,
Antimicrobial agents and chemotherapy,
R F Schinazi, and
C K Chu, and
B F Eriksson, and
J P Sommadossi, and
K J Doshi, and
F D Boudinot, and
B Oswald, and
H M McClure
November 1992,
Antimicrobial agents and chemotherapy,
