Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor.
A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a Ki of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (greater than 8000) in culture.
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
V J
VJ
Merluzzi
K D
KD
Hargrave
M
M
Labadia
K
K
Grozinger
M
M
Skoog
J C
JC
Wu
C K
CK
Shih
K
K
Eckner
S
S
Hattox
J
J
Adams
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D019829:Nevirapine; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine