title: Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.
abstract: 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.
authors.affiliation: Takeda California, 10410 Science Center Dr, San Diego, CA 92121, USA. anthony.gangloff@takeda.com
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Gangloff
authors.forename: Jason
authors.initials: J
authors.lastname: Brown
authors.forename: Ron
authors.initials: R
authors.lastname: de Jong
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.forename: Charles E
authors.initials: CE
authors.lastname: Grimshaw
authors.forename: Mark
authors.initials: M
authors.lastname: Hixon
authors.forename: Andy
authors.initials: A
authors.lastname: Jennings
authors.forename: Ruhi
authors.initials: R
authors.lastname: Kamran
authors.forename: Andre
authors.initials: A
authors.lastname: Kiryanov
authors.forename: Shawn
authors.initials: S
authors.lastname: O'Connell
authors.forename: Ewan
authors.initials: E
authors.lastname: Taylor
authors.forename: Phong
authors.initials: P
authors.lastname: Vu
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D048588:Benzoxazines; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
keywords: 1,4-Benzoxazin-3-one; Chemopotentiation; PARP-1; Poly(ADP-ribose)polymerase inhibitors; Structure-based drug design