The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1

Abstract Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. Compound 1a (9 b -(4-chlorophenyl)-1-(4-fluorobenzoyl)-1,2,3,9 b -tetrahydro-5 H -imidazo[2,1- a ]isoindol-5-one) was identified as an inhibitor of A and B strains of RSV targeting the fusion glycoprotein. SAR was developed by systematic exploration of the phenyl ( R 1 ) and benzoyl ( R 2 ) groups. Furthermore, introduction of a nitrogen at the 8-position of the tricyclic core resulted in active analogues with improved properties (aqueous solubility, protein binding and log  D ) and excellent rat pharmacokinetics (e.g., rat oral bioavailability of 89% for compound 17 ).