3,4-Dihydro-2-phenyl-2H-pyrano[2,3-b]pyridines with potent antirhinovirus activity.

A general synthesis to the title compounds 1, substituted in the 6-position and on the phenyl ring, is outlined. Eighteen analogues were compared with respect to in vitro activity against rhinovirus types 1A, 9, and 64. Compounds 1c and 1h, the 6-bromo- and 6-(methylsulfonyl)-3',4'-dichlorophenyl analogues, afforded median MIC50 values against 23 rhinovirus serotypes of 0.05 and 0.13 micrograms/mL, respectively. Mice dosed orally with 200 mg/kg of 1c or 1h exhibited serum levels well in excess of each compound's MIC50, indicating that some analogues have the potential to be orally effective drugs.

Antipicornavirus activity of substituted phenoxybenzenes and phenoxypyridines.

Phenoxybenzenes and phenoxypyridines were prepared and tested for the effect of substituents on antipicornavirus activity. The most active compound, 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (8), demonstrated broad-spectrum antipicornavirus activity. Compound 8 and several analogues each given orally prior to and during infection protected mice against an otherwise lethal challenge with coxsackievirus A21.

Antipicornavirus activity of some diaryl methanes and aralkylaminopyridines.

Sixteen diarylmethanes and ten aralkylaminopyridines were initially evaluated for their in vitro activity against rhinoviruses 1A, 2 and 64 and against coxsackievirus A21 and for their oral prophylactic and therapeutic activity in mice challenged with coxsackievirus A21. Based on these preliminary studies the diarylmethane (3,4-dichlorophenoxy)-(5 methylsulfonyl-2-pyridinyl)-methane and the aralkylaminopyridine (2-(3,4-dichlorobenzylamino)-5-methylsulfonylpyridine were compared with their oxygen bridged analogue 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)pyridine for in vitro activity against a larger number of picornaviruses and for their in vivo protective efficacy in dose response assays. All three compounds exhibit similar in vitro activity inhibiting 12 to 15 (52.2-65.3%) of the 23 picornaviruses tested at concentrations of less than 5.0 micrograms/ml. However, the aralkylaminopyridine was found to be the most active in vivo; significantly protecting coxsackievirus A21 challenged mice after a single oral dose of 37.5 mg/kg (P less than or equal to 0.05) and during a continuous oral dose regimen of as low as 18.8 mg/kg per day (P less than 0.01).

In vitro antiviral activity of the 6-substituted 2-(3',4'-dichlorophenoxy)-2H-pyrano[2,3-b]pyridines MDL 20,610, MDL 20,646, and MDL 20,957.

The 6-substituted 2-(3',4'-dichlorophenoxy)-2H-pyrano[2,3-b]pyridines MDL 20,610 (6-SO2CH3), MDL 20,646 (6-Br), and MDL 20,957 (6-Cl) are potent antirhinovirus compounds with median plaque 50% inhibitory concentrations (IC1/2s) of 0.03, 0.006, and 0.006 micrograms/ml, respectively, against the 32 serotypes evaluated. The 6-halogenated analogs produced 99% reductions in progeny virion yields at concentrations as low as 0.004 micrograms/ml. However, these analogs perturbated HeLa cell metabolism at lower concentrations (at or above 5 micrograms/ml) than did the 6-methylsulfonyl analog (at or above 20 micrograms/ml). Compound MDL 20,610 was also active against human, simian, and bovine rotaviruses (cytopathic effect IC1/2s of 0.8 to 1.5 micrograms/ml) and possessed variable enterovirus and paramyxovirus activity.