title: 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 (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 (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 logD) and excellent rat pharmacokinetics (e.g., rat oral bioavailability of 89% for compound 17).
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Silas
authors.initials: S
authors.lastname: Bond
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia. Electronic address: a.draffan@biota.com.au.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Draffan
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Fenner
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Lambert
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Chin Yu
authors.initials: CY
authors.lastname: Lim
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Lin
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Luttick
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Mitchell
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Nearn
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Sanford
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Pauline C
authors.initials: PC
authors.lastname: Stanislawski
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Tucker
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008561:Membrane Fusion / Q000187:drug effects*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles
keywords: Antiviral; Respiratory syncytial virus; Synthesis