1,4-Benzodiazepines as inhibitors of respiratory syncytial virus.
Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as a serious threat to patient groups with poorly functioning immune systems. Our approach to finding a novel inhibitor of this virus was to screen a 20 000-member diverse library in a whole cell XTT assay. Parallel assays were carried out in the absence of virus in order to quantify any associated cell toxicity. This identified 100 compounds with IC(50)'s less than 50 muM. A-33903 (18), a 1,4-benzodiazepine analogue, was chosen as the starting point for lead optimization. This molecule was moderately active and demonstrated good pharmacokinetic properties. The most potent compounds identified from this work were A-58568 (47), A-58569 (44), and A-62066 (46), where modifications to the aromatic substitution enhanced potency, and A-58175 (42), where the amide linker was modified.
Arrow Therapeutics Ltd, Britannia House, 7, Trinity Street, London, SE1 1DA, UK. mcarter@arrowt.co.uk
Malcolm C
MC
Carter
Dagmar G
DG
Alber
Robert C
RC
Baxter
Sian K
SK
Bithell
Jo
J
Budworth
Ann
A
Chubb
G Stuart
GS
Cockerill
Verity C L
VC
Dowdell
Elisa A
EA
Henderson
Sally J
SJ
Keegan
Richard D
RD
Kelsey
Michael J
MJ
Lockyer
Jeremy N
JN
Stables
Lara J
LJ
Wilson
Kenneth L
KL
Powell
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D001569:Benzodiazepines