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.