1,4-benzodiazepines as inhibitors of respiratory syncytial virus. The identification of a clinical candidate.
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.
Henderson
Elisa A
EA
Arrow Therapeutics, Britannia House, 7 Trinity Street, London, SE1 1DA, United Kingdom. ehenderson@arrowt.co.uk
Alber
Dagmar G
DG
Baxter
Robert C
RC
Bithell
Sian K
SK
Budworth
Joanna
J
Carter
Malcolm C
MC
Chubb
Ann
A
Cockerill
G Stuart
GS
Dowdell
Verity C L
VC
Fraser
Ian J
IJ
Harris
Robert A
RA
Keegan
Sally J
SJ
Kelsey
Richard D
RD
Lumley
James A
JA
Stables
Jeremy N
JN
Weerasekera
Natasha
N
Wilson
Lara J
LJ
Powell
Kenneth L
KL
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
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