title: Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor.
abstract: 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.
authors.affiliation: Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Poppe
authors.forename: D E
authors.initials: DE
authors.lastname: Slade
authors.forename: K T
authors.initials: KT
authors.lastname: Chong
authors.forename: R R
authors.initials: RR
authors.lastname: Hinshaw
authors.forename: P J
authors.initials: PJ
authors.lastname: Pagano
authors.forename: M
authors.initials: M
authors.lastname: Markowitz
authors.forename: D D
authors.initials: DD
authors.lastname: Ho
authors.forename: H
authors.initials: H
authors.lastname: Mo
authors.forename: R R
authors.initials: RR
authors.lastname: Gorman
authors.forename: T J
authors.initials: TJ
authors.lastname: Dueweke
authors.forename: S
authors.initials: S
authors.lastname: Thaisrivongs
authors.forename: W G
authors.initials: WG
authors.lastname: Tarpley
mesh_terms: 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
chemical_list: 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