Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability.

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)-1 H -benzimidazol-2-yl]methyl]-2 H -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.