title: Discovery of novel benzothienoazepine derivatives as potent inhibitors of respiratory syncytial virus.
abstract: The development of novel non-nucleoside inhibitors of the RSV polymerase complex is of significant clinical interest. Compounds derived from the benzothienoazepine core, such as AZ-27, are potent inhibitors of RSV viruses of the A-subgroup, but are only moderately active against the B serotype and as yet have not demonstrated activity in vivo. Herein we report the discovery of several novel families of C-2 arylated benzothienoazepine derivatives that are highly potent RSV polymerase inhibitors and reveal an exemplary structure, compound 4a, which shows low nanomolar activity against both RSV A and B viral subtypes. Furthermore, this compound is effective at suppressing viral replication, when administered intranasally, in a rodent model of RSV infection. These results suggest that compounds belonging to this chemotypes have the potential to provide superior anti-RSV agents than those currently available for clinical use.
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom. Electronic address: e.fordyce@sygnaturediscovery.com.
authors.forename: Euan A F
authors.initials: EAF
authors.lastname: Fordyce
authors.affiliation: Pulmocide Ltd., Imperial BioIncubator, Level 1 Bessemer Building (RSM), Imperial College, London SW7 2BP, United Kingdom.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Brookes
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Lise-Ciana
authors.affiliation: Pulmocide Ltd., Imperial BioIncubator, Level 1 Bessemer Building (RSM), Imperial College, London SW7 2BP, United Kingdom.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Coates
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom.
authors.forename: S Fraser
authors.initials: SF
authors.lastname: Hunt
authors.affiliation: Pulmocide Ltd., Imperial BioIncubator, Level 1 Bessemer Building (RSM), Imperial College, London SW7 2BP, United Kingdom. Electronic address: kaz@pulmocide.com.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
authors.affiliation: CompChem Resource, Old Cottage Hospital, Homend, Ledbury, Herefordshire HR8 1ED, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: King-Underwood
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom.
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Onions
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom.
authors.forename: Guillaume F
authors.initials: GF
authors.lastname: Parra
authors.affiliation: Pulmocide Ltd., Imperial BioIncubator, Level 1 Bessemer Building (RSM), Imperial College, London SW7 2BP, United Kingdom.
authors.forename: Garth
authors.initials: G
authors.lastname: Rapeport
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sherbukhin
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Stockwell
authors.affiliation: Pulmocide Ltd., Imperial BioIncubator, Level 1 Bessemer Building (RSM), Imperial College, London SW7 2BP, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Strong
authors.affiliation: Sygnature Discovery Ltd., BioCity, Nottingham NG1 1GF, United Kingdom.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Thomas
authors.affiliation: Pulmocide Ltd., Imperial BioIncubator, Level 1 Bessemer Building (RSM), Imperial College, London SW7 2BP, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Murray
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000201:enzymology; D065288:Serogroup; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D001381:Azepines; D012321:DNA-Directed RNA Polymerases
keywords: Antiviral; Polymerase inhibitor; RSV