1,4-benzodiazepines as inhibitors of respiratory syncytial virus. The identification of a clinical candidate

  • J Med Chem. 2007 Apr 5;50(7):1685-92. doi: 10.1021/jm060747l.
Elisa A Henderson  1 ,  Dagmar G Alber ,  Robert C Baxter ,  Sian K Bithell ,  Joanna Budworth ,  Malcolm C Carter ,  Ann Chubb ,  G Stuart Cockerill ,  Verity C L Dowdell ,  Ian J Fraser ,  Robert A Harris ,  Sally J Keegan ,  Richard D Kelsey ,  James A Lumley ,  Jeremy N Stables ,  Natasha Weerasekera ,  Lara J Wilson ,  Kenneth L Powell
Affiliations
  • 1. Arrow Therapeutics, Britannia House, 7 Trinity Street, London, SE1 1DA, United Kingdom. [email protected]
PMID: 17341059 DOI: 10.1021/jm060747l
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.

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