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1,4-Benzodiazepines as inhibitors of respiratory syncytial virus

Carter, M.C.; Alber, D.G.; Baxter, R.C.; Bithell, S.K.; Budworth, J.; Chubb, A.; Cockerill, G.S.; Dowdell, V.C.L.; Henderson, E.A.; Keegan, S.J.; Kelsey, R.D.; Lockyer, M.J.; Stables, J.N.; Wilson, L.J.; Powell, K.L.

Authors

M.C. Carter

D.G. Alber

R.C. Baxter

S.K. Bithell

J. Budworth

A. Chubb

G.S. Cockerill

V.C.L. Dowdell

E.A. Henderson

S.J. Keegan

R.D. Kelsey

M.J. Lockyer

J.N. Stables

L.J. Wilson

K.L. Powell



Abstract

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 IC50's less than 50 μM. 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.

Citation

Carter, M., Alber, D., Baxter, R., Bithell, S., Budworth, J., Chubb, A., …Powell, K. (2006). 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus. Journal of Medicinal Chemistry, 49(7), 2311-2319. https://doi.org/10.1021/jm051185t

Journal Article Type Article
Publication Date Apr 1, 2006
Deposit Date Jan 24, 2014
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 49
Issue 7
Pages 2311-2319
DOI https://doi.org/10.1021/jm051185t

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