title: In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity.
abstract: Pirodavir (R 77975) is the prototype of a novel class of broad-spectrum antipicornavirus compounds. Although its predecessor, R 61837, a substituted phenyl-pyridazinamine, was effective in inhibiting 80% of 100 serotypes tested (EC80) at concentrations above 32 micrograms/ml, pirodavir inhibits the same percentage of viruses at 0.064 micrograms/ml. Whereas R 61837 was active almost exclusively against rhinovirus serotypes of antiviral group B, pirodavir is broad spectrum in that it is highly active against both group A and group B rhinovirus serotypes. Pirodavir is also effective in inhibiting 16 enteroviruses, with an EC80 of 1.3 micrograms/ml. Susceptible rhinovirus serotypes were rendered noninfectious by direct contact with the antiviral compound. Their infectivity was not restored by dilution of virus-drug complexes, but was regained by organic solvent extraction of the compound for most serotypes. Neutralized viruses became stabilized to acid and heat, strongly suggesting a direct interaction of the compounds with viral capsid proteins. Mutants resistant to R 61837 (up to 85 times the MIC) were shown to bear some cross-resistance (up to 23 times the MIC) to the new compound, indicating that pirodavir also binds into the hydrophobic pocket beneath the canyon floor of rhinoviruses. Pirodavir acts at an early stage of the viral replication cycle (up to 40 min after infection) and reduces the yield of selected rhinoviruses 1,000- to 100,000-fold in a single round of replication. The mode of action appears to be serotype specific, since pirodavir was able to inhibit the adsorption of human rhinovirus 9 but not that of human rhinovirus 1A. Pirodavir is a novel capsid-binding antipicornavirus agent with potent in vitro activity against both group A and group B rhinovirus serotypes.
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Andries
authors.forename: B
authors.initials: B
authors.lastname: Dewindt
authors.forename: J
authors.initials: J
authors.lastname: Snoeks
authors.forename: R
authors.initials: R
authors.lastname: Willebrords
authors.forename: K
authors.initials: K
authors.lastname: van Eemeren
authors.forename: R
authors.initials: R
authors.lastname: Stokbroekx
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D004770:Enterovirus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D012229:Rhinovirus / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000998:Antiviral Agents; D010880:Piperidines; D011724:Pyridazines; C057389:R 61837; C074589:pirodavir