title: Respiratory syncytial virus fusion inhibitors. Part 3: Water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo.
abstract: The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration. These results established the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration.
authors.affiliation: Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5, Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Kuo-Long
authors.initials: KL
authors.lastname: Yu
authors.forename: Xiangdong Alan
authors.initials: XA
authors.lastname: Wang
authors.forename: Rita L
authors.initials: RL
authors.lastname: Civiello
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Trehan
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Pearce
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yin
authors.forename: Keith D
authors.initials: KD
authors.lastname: Combrink
authors.forename: H Belgin
authors.initials: HB
authors.lastname: Gulgeze
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Kadow
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cianci
authors.forename: Junius
authors.initials: J
authors.lastname: Clarke
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Genovesi
authors.forename: Ivette
authors.initials: I
authors.lastname: Medina
authors.forename: Lucinda
authors.initials: L
authors.lastname: Lamb
authors.forename: Philip R
authors.initials: PR
authors.lastname: Wyde
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008561:Membrane Fusion / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000502:physiology*; D016205:Sigmodontinae; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
chemical_list: D000588:Amines; D000998:Antiviral Agents; D001562:Benzimidazoles; D014867:Water; C053110:benzimidazol-2-one