L-696,229 specifically inhibits human immunodeficiency virus type 1 reverse transcriptase and possesses antiviral activity in vitro.
L-696,229 (3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2 (1H)-one) is a specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity that possesses antiviral activity in cell culture (W.S. Saari, J.M. Hoffman, J.S. Wai, T.E. Fisher, C.S. Rooney, A.M. Smith, C.M. Thomas, M. E. Goldman, J. A. O'Brien, J. H. Nunberg, J. C. Quintero, W. A. Schleif, E. A. Emini, and P. S. Anderson, J. Med. Chem. 34:2922-2925, 1991). In the present study, the RT-inhibitory activity and antiviral properties were characterized in detail. The inhibition of RT activity was template-primer dependent with 50% inhibitory concentrations of 0.018 to 0.50 microM and was noncompetitive with respect to deoxynucleoside triphosphates. L-696,229 inhibited RT activity in a mutually exclusive manner with respect to either phosphonoformate or azidothymidine triphosphate and was a weak partial inhibitor of the RNase H activity associated with HIV-1 RT. The compound did not significantly inhibit other retroviral or cellular polymerases at 300 microM.L-696,229 inhibited the spread of HIV-1 infection in cell cultures with all cell types and viral isolates tested, including human peripheral blood mononuclear cells and a virus isolate resistant to azidothymidine.
Goldman
M E
ME
Department of New Lead Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486-0004.
O'Brien
J A
JA
Ruffing
T L
TL
Nunberg
J H
JH
Schleif
W A
WA
Quintero
J C
JC
Siegl
P K
PK
Hoffman
J M
JM
Smith
A M
AM
Emini
E A
EA
D001583:Benzoxazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D054306:Dideoxynucleotides; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D011506:Proteins / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides / Q000494:pharmacology; D015215:Zidovudine / Q000031:analogs & derivatives / Q000494:pharmacology
D001583:Benzoxazoles; D054306:Dideoxynucleotides; D011506:Proteins; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C076250:L 696229; D015215:Zidovudine; C052873:zidovudine triphosphate