Respiratory syncytial virus fusion inhibitors. Part 3: Water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo.
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.
Yu
Kuo-Long
KL
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5, Research Parkway, Wallingford, CT 06492, USA.
Wang
Xiangdong Alan
XA
Civiello
Rita L
RL
Trehan
Ashok K
AK
Pearce
Bradley C
BC
Yin
Zhiwei
Z
Combrink
Keith D
KD
Gulgeze
H Belgin
HB
Zhang
Yi
Y
Kadow
Kathleen F
KF
Cianci
Christopher W
CW
Clarke
Junius
J
Genovesi
Eugene V
EV
Medina
Ivette
I
Lamb
Lucinda
L
Wyde
Philip R
PR
Krystal
Mark
M
Meanwell
Nicholas A
NA
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*
D000588:Amines; D000998:Antiviral Agents; D001562:Benzimidazoles; D014867:Water; C053110:benzimidazol-2-one