A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer templates.
R82913, (+)-S-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)- imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (a TIBO derivative), inhibited the replication of thirteen different strains of HIV-1 in CEM cells with a median IC50 of 0.15 microM. The concentration of compound that killed 50% of the cells was much higher (46 microM), indicating that R82913 has a high selectivity index. R82913 was 20-fold more potent than AZT-TP in the inhibition of HIV-1 reverse transcriptase in an assay using a naturally occurring template (ribosomal RNA) that more accurately resembles native viral RNA than a synthetic homopolymer. With this template, R82913 inhibited HIV-1 reverse transcriptase with an ID50 (0.01 microM) that is equal to, or lower than, the IC50 for this compound in all of our cell culture assays (0.01-0.65 microM). R82913 has no effect on the replication of HIV-2 in CEM cells and does not inhibit the reverse transcriptase from this virus.
White
E L
EL
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama.
Buckheit
R W
RW
Ross
L J
LJ
Germany
J M
JM
Andries
K
K
Pauwels
R
R
Janssen
P A
PA
Shannon
W M
WM
Chirigos
M A
MA
D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects* / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology*; D008969:Molecular Sequence Data; D012191:Retroviridae Proteins / Q000037:antagonists & inhibitors*; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic; D015215:Zidovudine / Q000494:pharmacology
D007093:Imidazoles; D012191:Retroviridae Proteins; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; D015215:Zidovudine; C067413:R-82913