Abstract
A series of benzimidazole-based inhibitors of respiratory syncytial virus (RSV) fusion were optimized for antiviral potency, membrane permeability and metabolic stability in human liver microsomes. 1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]methyl]-2H-imidazo[4,5-c]pyridin-2-one (6m, BMS-433771) was identified as a potent RSV inhibitor demonstrating good bioavailability in the mouse, rat, dog and cynomolgus monkey that demonstrated antiviral activity in the BALB/c and cotton rat models of infection following oral administration.
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology*
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Biological Availability
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Caco-2 Cells
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Chemical Phenomena
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Chemistry, Physical
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Cytopathogenic Effect, Viral / drug effects
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Dogs
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Half-Life
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Humans
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In Vitro Techniques
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Macaca fascicularis
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver / drug effects
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Rats
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Respiratory Syncytial Virus Infections / drug therapy
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Respiratory Syncytial Virus Infections / virology
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Respiratory Syncytial Virus, Human / drug effects*
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Sigmodontinae
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Structure-Activity Relationship
Substances
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Antiviral Agents
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BMS 433771
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Benzimidazoles