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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 16; pp. 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: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2013; Elsevier
• Subjects: 1,4-Benzoxazin-3-one; Animals; Benzoxazines - chemistry; Benzoxazines - pharmacology; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Chemopotentiation; Drug Design; drugs; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Life Sciences & Biomedicine; Mice; Mice, Nude; Molecular Structure; PARP-1; Pharmacology & Pharmacy; Physical Sciences; Poly(ADP-ribose) Polymerase Inhibitors; Science & Technology; Structure-based drug design; Chemopotentiation; Poly(ADP-ribose)polymerase inhibitors; Structure-based drug design; 1,4-Benzoxazin-3-one; PARP-1; TEMOZOLOMIDE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.055

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.