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.
Carter
Malcolm C
MC
Arrow Therapeutics Ltd, Britannia House, 7, Trinity Street, London, SE1 1DA, UK. mcarter@arrowt.co.uk
Alber
Dagmar G
DG
Baxter
Robert C
RC
Bithell
Sian K
SK
Budworth
Jo
J
Chubb
Ann
A
Cockerill
G Stuart
GS
Dowdell
Verity C L
VC
Henderson
Elisa A
EA
Keegan
Sally J
SJ
Kelsey
Richard D
RD
Lockyer
Michael J
MJ
Stables
Jeremy N
JN
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* / 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