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 (EC.) at concentrations above 32 ,ug/ml, pirodavir inhibits the same percentage of viruses at 0.064 ,ug/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 ECgo of 1.3 ,ug/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.

The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperidine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.

R 61837 or 3-methoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine is a new and potent inhibitor of rhinoviruses at concentrations not inhibitory to HeLa cell growth. Different rhinovirus serotypes varied widely in their susceptibility to the antiviral agent. The MICs for 50% CPE reduction ranged from 0.004 to 15 micrograms/ml. The yields of the most susceptible serotypes were reduced by a factor of 1,000 to 10,000 after single round high multiplicity infections in presence of low concentrations of the compound. The inactivation of some but not all serotypes in a time-, concentration- and temperature-dependent way by R 61837 indicated a direct interaction between the drug and the viral particles. The antiviral activity of the compound was confirmed in the human target cells for rhinoviruses by experiments using nasal polyp explant cultures.

To study the bioisosteric replacement of a 2-pyridyl ring for a phenyl nucleus in astemizole, a series of N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amines was synthesized and evaluated. The title compounds were obtained starting from either 8a or 8b by four synthetic methods. The in vivo antihistamine activity was evaluated by the compound 48/80-induced lethality test in rats and the histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. Compound 37, the isostere of astemizole, showed the most potent antihistaminic properties in the rat. However, astemizole is superior to 37 as to duration of action and total potency.

No abstract

No abstract

The synthesis of a series of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-ami nes and the preliminary evaluation of their in vivo antihistamine activity are described. The title compounds were obtained starting from either 1, 4, 10, or 55 by different synthetic methods. Substitution on the phenyl nucleus of the benzimidazole ring (84-87) was achieved by two different approaches. The in vivo antihistamine activity was evaluated by the compound 48/80 induced lethality test in rats and the antihistamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action was studied in the guinea pig for three compounds (4, 51, and 55). Compound 51, "astemizole", was also studied in histamine- and serotonin-induced cutaneous reaction and for mydriatic activity in the rat and tested for peripheral and central effects not related to histamine antagonism in a variety of systems. Astemizole has been selected for clinical investigation.

Stokbroekx R.A., M.G.M. Luyckx, J.J.M. Willerns, M. Janssen, J.O.M.M. Bracke, R.L.P. Joosen, and J.P. Van Wauwe: Levocabastine (R 50547): The prototype of a chemical series of compounds with specific HI-antihistaminic activity. Drug Dev. Res. 8:87-93, 1986.The synthesis and the histamine HI antagonism of four racemates of l-[cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid, termed R 48756, R 49389, R 49429, and R 49549, are described. R48756 (cabastine) was found to be the most potent compound, with oral ED50 values of 0.002-0.003 mglkg in both the histamineinduced lethality test (guinea pigs) and the compound 48/80 assay (rats). Upon resolution of cabastine into its two optical isomers, levocabastine (R 50547) after oral administration in guinea pigs was about four times (1 hr) to 90 times (24 hr) more potent than dextrocabastine (R 50554). Protection from dyspnea, induced by histamine aerosols, was obtained with 0.005 mglkg of levocabastine, whereas a dose of 2.5 mglkg, failed to protect guinea pigs from dyspnea induced by serotonin or acetylcholine aerosols.