Oral efficacy of a respiratory syncytial virus inhibitor in rodent models of infection.
BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C. Cianci, K. Y. Yu, K. Combrink, N. Sin, B. Pearce, A. Wang, R. Civiello, S. Voss, G. Luo, K. Kadow, E. Genovesi, B. Venables, H. Gulgeze, A. Trehan, J. James, L. Lamb, I. Medina, J. Roach, Z. Yang, L. Zadjura, R. Colonno, J. Clark, N. Meanwell, and M. Krystal, Antimicrob. Agents Chemother. 48:413-422, 2004). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was approximately 7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.
Cianci
Christopher
C
The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
Genovesi
Eugene V
EV
Lamb
Lucinda
L
Medina
Ivette
I
Yang
Zheng
Z
Zadjura
Lisa
L
Yang
Hyekyung
H
D'Arienzo
Celia
C
Sin
Ny
N
Yu
Kuo-Long
KL
Combrink
Keith
K
Li
Zhufang
Z
Colonno
Richard
R
Meanwell
Nicholas
N
Clark
Junius
J
Krystal
Mark
M
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects; D016205:Sigmodontinae; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles; D014760:Viral Fusion Proteins