A nonnucleoside reverse transcriptase inhibitor active on human immunodeficiency virus type 1 isolates resistant to related inhibitors.
Pyridinone derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and HIV-1 replication in cell culture. However, the potential clinical usefulness of these compounds as monotherapeutic agents may be limited by the selection of inhibitor-resistant viral variants. Resistance in cell culture is due primarily to mutational alterations at RT amino acid residues 103 and 181. A recombinant HIV-1 RT containing both of these mutations was used to screen a panel of pyridinone analogs for inhibitory activity. L-696,229 and L-697,661, pyridinones currently undergoing clinical evaluation, were more than 4,000-fold weaker against the mutant enzyme than against the wild-type enzyme. In contrast, one derivative of L-696,229, L-702,019 (3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyrid in-2(1H)-thione), showed only three-fold different potencies against the two enzymes. L-702,019 was also a potent inhibitor of the replication of mutant HIV-1 containing the individual mutations at amino acid 103 or 181 as well as of clinical isolates resistant to L-697,661 and L-696,229. Isolation and analysis of resistant viral variants in cell culture showed that significant resistance to L-702,019 could be engendered only by multiple amino acid substitutions in RT. Accordingly, these studies demonstrated the potential of identifying second-generation specific HIV-1 RT inhibitors that can overcome the viral resistance selected by the first generation of inhibitors.
Goldman
M E
ME
Department of New Lead Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486.
O'Brien
J A
JA
Ruffing
T L
TL
Schleif
W A
WA
Sardana
V V
VV
Byrnes
V W
VW
Condra
J H
JH
Hoffman
J M
JM
Emini
E A
EA
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D011728:Pyridones / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors
D000998:Antiviral Agents; D001583:Benzoxazoles; D011728:Pyridones; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; C076250:L 696229; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase