title: Antiviral activity of GW678248, a novel benzophenone nonnucleoside reverse transcriptase inhibitor.
abstract: The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC(50)s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC(50) of < or =21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC(50) of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml alpha-1 acid glycoprotein increased the IC(50) approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents.
authors.affiliation: Department of Virology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ferris
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hazen
authors.forename: Grace B
authors.initials: GB
authors.lastname: Roberts
authors.forename: Marty H
authors.initials: MH
authors.lastname: St Clair
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Chan
authors.forename: Karen R
authors.initials: KR
authors.lastname: Romines
authors.forename: George A
authors.initials: GA
authors.lastname: Freeman
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Tidwell
authors.forename: Lee T
authors.initials: LT
authors.lastname: Schaller
authors.forename: Jill R
authors.initials: JR
authors.lastname: Cowan
authors.forename: Steven A
authors.initials: SA
authors.lastname: Short
authors.forename: Kurt L
authors.initials: KL
authors.lastname: Weaver
authors.forename: Dean W
authors.initials: DW
authors.lastname: Selleseth
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Moniri
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Boone
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001577:Benzophenones / Q000737:chemistry*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000821:virology; D015394:Molecular Structure; D009154:Mutation; D009961:Orosomucoid / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012709:Serum Albumin / Q000378:metabolism; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D001577:Benzophenones; D009961:Orosomucoid; D018894:Reverse Transcriptase Inhibitors; D012709:Serum Albumin; C047723:benzophenone