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. 1989 Dec;33(12):2069–2074. doi: 10.1128/aac.33.12.2069

In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug.

M G Woods 1, G D Diana 1, M C Rogge 1, M J Otto 1, F J Dutko 1, M A McKinlay 1
PMCID: PMC172823  PMID: 2559655

Abstract

WIN 54954 (5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl]-3- methylisoxazole) is a new member of the class of broad-spectrum antipicornavirus compounds known to bind in a hydrophobic pocket within virion capsid protein VP1. In plaque reduction assays, WIN 54954 reduced plaque formation of 50 of 52 rhinovirus serotypes (MICs ranged from 0.007 to 2.2 micrograms/ml). A concentration of 0.28 microgram/ml was effective in inhibiting 80% of the 52 serotypes tested (EC80). WIN 54954 was also effective in inhibiting 15 commonly isolated enteroviruses, with an EC80 of 0.06 microgram/ml. Furthermore, WIN 54954 was effective in reducing the yield of two selected enteroviruses in cell culture by 90% at concentrations approximately equal to their MICs. The therapeutic efficacy of intragastrically administered WIN 54954 was assessed in suckling mice infected with coxsackievirus A-9 or echovirus type 9 (Barty) 2.5 days prior to initiation of therapy. Single daily doses of 2 and 100 mg/kg protected 50% of the mice from developing paralysis (PD50) following infection with coxsackievirus A-9 and echovirus-9, respectively. At the PD50 doses for these two viruses, levels of WIN 54954 in serum were maintained above the in vitro MICs for a significant portion of the dosing interval. The dose-dependent reduction in viral titers observed in coxsackievirus A-9-infected mice correlated well with the therapeutic dose response. The potency and spectrum of WIN 54954 make it a potentially useful compound for the treatment of human enterovirus and rhinovirus infections.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Al-Nakib W., Tyrrell D. A. A 'new' generation of more potent synthetic antirhinovirus compounds: comparison of their MICs and their synergistic interactions. Antiviral Res. 1987 Nov;8(4):179–187. doi: 10.1016/0166-3542(87)90072-6. [DOI] [PubMed] [Google Scholar]
  2. Andries K., Dewindt B., De Brabander M., Stokbroekx R., Janssen P. A. In vitro activity of R 61837, a new antirhinovirus compound. Arch Virol. 1988;101(3-4):155–167. doi: 10.1007/BF01310997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Badger J., Minor I., Kremer M. J., Oliveira M. A., Smith T. J., Griffith J. P., Guerin D. M., Krishnaswamy S., Luo M., Rossmann M. G. Structural analysis of a series of antiviral agents complexed with human rhinovirus 14. Proc Natl Acad Sci U S A. 1988 May;85(10):3304–3308. doi: 10.1073/pnas.85.10.3304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bültmann B. D., Eggers H. J., Galle J., Haferkamp O. Age dependence of paralysis induced by echovirus type 9 in infant mice. J Infect Dis. 1983 Jun;147(6):999–1005. doi: 10.1093/infdis/147.6.999. [DOI] [PubMed] [Google Scholar]
  5. Diana G. D., Cutcliffe D., Oglesby R. C., Otto M. J., Mallamo J. P., Akullian V., McKinlay M. A. Synthesis and structure-activity studies of some disubstituted phenylisoxazoles against human picornavirus. J Med Chem. 1989 Feb;32(2):450–455. doi: 10.1021/jm00122a027. [DOI] [PubMed] [Google Scholar]
  6. Fox M. P., Otto M. J., McKinlay M. A. Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug. Antimicrob Agents Chemother. 1986 Jul;30(1):110–116. doi: 10.1128/aac.30.1.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. MELNICK J. L., GODMAN G. C. Pathogenesis of coxsackie virus infection; multiplication of virus and evolution of the muscle lesion in mice. J Exp Med. 1951 Mar;93(3):247–266. doi: 10.1084/jem.93.3.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. McKinlay M. A., Frank J. A., Jr, Benziger D. P., Steinberg B. A. Use of WIN 51711 to prevent echovirus type 9-induced paralysis in suckling mice. J Infect Dis. 1986 Oct;154(4):676–681. doi: 10.1093/infdis/154.4.676. [DOI] [PubMed] [Google Scholar]
  9. McKinlay M. A., Steinberg B. A. Oral efficacy of WIN 51711 in mice infected with human poliovirus. Antimicrob Agents Chemother. 1986 Jan;29(1):30–32. doi: 10.1128/aac.29.1.30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Otto M. J., Fox M. P., Fancher M. J., Kuhrt M. F., Diana G. D., McKinlay M. A. In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother. 1985 Jun;27(6):883–886. doi: 10.1128/aac.27.6.883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Pevear D. C., Fancher M. J., Felock P. J., Rossmann M. G., Miller M. S., Diana G., Treasurywala A. M., McKinlay M. A., Dutko F. J. Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors. J Virol. 1989 May;63(5):2002–2007. doi: 10.1128/jvi.63.5.2002-2007.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Sperber S. J., Hayden F. G. Chemotherapy of rhinovirus colds. Antimicrob Agents Chemother. 1988 Apr;32(4):409–419. doi: 10.1128/aac.32.4.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Strikas R. A., Anderson L. J., Parker R. A. Temporal and geographic patterns of isolates of nonpolio enterovirus in the United States, 1970-1983. J Infect Dis. 1986 Feb;153(2):346–351. doi: 10.1093/infdis/153.2.346. [DOI] [PubMed] [Google Scholar]
  14. Zeichhardt H., Otto M. J., McKinlay M. A., Willingmann P., Habermehl K. O. Inhibition of poliovirus uncoating by disoxaril (WIN 51711). Virology. 1987 Sep;160(1):281–285. doi: 10.1016/0042-6822(87)90075-4. [DOI] [PubMed] [Google Scholar]
  15. al-Nakib W., Higgins P. G., Barrow G. I., Tyrrell D. A., Andries K., Vanden Bussche G., Taylor N., Janssen P. A. Suppression of colds in human volunteers challenged with rhinovirus by a new synthetic drug (R61837). Antimicrob Agents Chemother. 1989 Apr;33(4):522–525. doi: 10.1128/aac.33.4.522. [DOI] [PMC free article] [PubMed] [Google Scholar]

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