title: 1,4-benzodiazepines as inhibitors of respiratory syncytial virus. The identification of a clinical candidate.
abstract: Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. Racemic 1,4-benzodiazepines show potent anti-RSV activity in vitro. Anti-RSV evaluation of 3-position R- and S-benzodiazepine enantiomers and subsequent optimization of this series resulted in selection of a clinical candidate. Antiviral activity was found to reside mainly in the S-enantiomer, and the R-enantiomers were consistently less active against RSV. Analogues of 1,4-(S)-benzodiazepine were synthesized as part of the lead optimization program at Arrow and tested in the XTT assay. From this exercise, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-urea, 17b (RSV-604) was identified as a clinical candidate, exhibiting potent anti-RSV activity in the XTT assay, which was confirmed in secondary assays. Compound 17b also possessed a good pharmacokinetic profile and has now progressed into the clinic.
authors.affiliation: Arrow Therapeutics, Britannia House, 7 Trinity Street, London, SE1 1DA, United Kingdom. ehenderson@arrowt.co.uk
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Henderson
authors.forename: Dagmar G
authors.initials: DG
authors.lastname: Alber
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
authors.forename: Sian K
authors.initials: SK
authors.lastname: Bithell
authors.forename: Joanna
authors.initials: J
authors.lastname: Budworth
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Carter
authors.forename: Ann
authors.initials: A
authors.lastname: Chubb
authors.forename: G Stuart
authors.initials: GS
authors.lastname: Cockerill
authors.forename: Verity C L
authors.initials: VC
authors.lastname: Dowdell
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Fraser
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Keegan
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kelsey
authors.forename: James A
authors.initials: JA
authors.lastname: Lumley
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Stables
authors.forename: Natasha
authors.initials: N
authors.lastname: Weerasekera
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Wilson
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Powell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
chemical_list: C519521:1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)urea; D000998:Antiviral Agents; D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D001569:Benzodiazepines