Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor.
PNU-140690 is a member of a new class of nonpeptidic human immunodeficiency virus (HIV) protease inhibitors (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones) discovered by structure-based design. PNU-140690 has excellent potency against a variety of HIV type 1 (HIV-1) laboratory strains and clinical isolates, including those resistant to the reverse transcriptase inhibitors zidovudine or delavirdine. When combined with either zidovudine or delavirdine, PNU-140690 contributes to synergistic antiviral activity. PNU-140690 is also highly active against HIV-1 variants resistant to peptidomimetic protease inhibitors, underscoring the structural distinctions between PNU-140690 and substrate analog protease inhibitors. PNU-140690 retains good antiviral activity in vitro in the presence of human plasma proteins, and preclinical pharmacokinetic studies revealed good oral bioavailability. Accordingly, PNU-140690 is a candidate for clinical evaluation.
Poppe
S M
SM
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
Slade
D E
DE
Chong
K T
KT
Hinshaw
R R
RR
Pagano
P J
PJ
Markowitz
M
M
Ho
D D
DD
Mo
H
H
Gorman
R R
RR
Dueweke
T J
TJ
Thaisrivongs
S
S
Tarpley
W G
WG
D019380:Anti-HIV Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D020008:Delavirdine; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D011753:Pyrones; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D015215:Zidovudine; D020008:Delavirdine; C107201:tipranavir