title: Orally active fusion inhibitor of respiratory syncytial virus.
abstract: BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.
authors.affiliation: The Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cianci
authors.forename: Kuo-Long
authors.initials: KL
authors.lastname: Yu
authors.forename: Keith
authors.initials: K
authors.lastname: Combrink
authors.forename: Ny
authors.initials: N
authors.lastname: Sin
authors.forename: Bradley
authors.initials: B
authors.lastname: Pearce
authors.forename: Alan
authors.initials: A
authors.lastname: Wang
authors.forename: Rita
authors.initials: R
authors.lastname: Civiello
authors.forename: Stacey
authors.initials: S
authors.lastname: Voss
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Luo
authors.forename: Kathy
authors.initials: K
authors.lastname: Kadow
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Genovesi
authors.forename: Brian
authors.initials: B
authors.lastname: Venables
authors.forename: Hatice
authors.initials: H
authors.lastname: Gulgeze
authors.forename: Ashok
authors.initials: A
authors.lastname: Trehan
authors.forename: Jennifer
authors.initials: J
authors.lastname: James
authors.forename: Lucinda
authors.initials: L
authors.lastname: Lamb
authors.forename: Ivette
authors.initials: I
authors.lastname: Medina
authors.forename: Julia
authors.initials: J
authors.lastname: Roach
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lisa
authors.initials: L
authors.lastname: Zadjura
authors.forename: Richard
authors.initials: R
authors.lastname: Colonno
authors.forename: Junius
authors.initials: J
authors.lastname: Clark
authors.forename: Nicholas
authors.initials: N
authors.lastname: Meanwell
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D024882:Drug Resistance, Viral; D005838:Genotype; D015726:Giant Cells / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000235:genetics; D013696:Temperature; D014760:Viral Fusion Proteins / Q000096:biosynthesis; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000096:biosynthesis
chemical_list: D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles; D018076:DNA, Complementary; D014760:Viral Fusion Proteins; D014764:Viral Proteins