Journal article
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
S Bond, AG Draffan, JE Fenner, J Lambert, CY Lim, B Lin, A Luttick, JP Mitchell, CJ Morton, RH Nearn, V Sanford, PC Stanislawski, SP Tucker
Bioorganic and Medicinal Chemistry Letters | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2015
Abstract
Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. Compound 1a (9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-1,2,3,9b-tetrahydro-5H-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 (R1) and benzoyl (R2) 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).
Grants
Funding Acknowledgements
Physicochemical, metabolic and pharmacokinetic experiments were conducted at the Centre for Drug Candidate Optimisation, Monash University (Melbourne, Australia). The authors are grateful to Penelope Mayes for assistance with the preparation of this manuscript. We acknowledge the financial assistance of a START grant from the Australian Government.