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.