Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors

Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-08, Vol.23 (16), p.4501-4505
Main Authors: Gangloff, Anthony R., Brown, Jason, de Jong, Ron, Dougan, Douglas R., Grimshaw, Charles E., Hixon, Mark, Jennings, Andy, Kamran, Ruhi, Kiryanov, Andre, O’Connell, Shawn, Taylor, Ewan, Vu, Phong
Format: Article
Language:English
Subjects:
1,4-Benzoxazin-3-one
Animals
Benzoxazines - chemistry
Benzoxazines - pharmacology
Cell Line, Tumor
chemistry
Chemopotentiation
Drug Design
drugs
Enzyme Activation - drug effects
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Mice
Mice, Nude
Molecular Structure
PARP-1
Poly(ADP-ribose) Polymerase Inhibitors
Structure-based drug design
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Summary:Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.06.055