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

Anthony R Gangloff; Jason Brown; Ron de Jong; Douglas R Dougan; Charles E Grimshaw; Mark Hixon; Andy Jennings; Ruhi Kamran; Andre Kiryanov; Shawn O'Connell; Ewan Taylor; Phong Vu

doi:10.1016/j.bmcl.2013.06.055

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

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4501-5. doi: 10.1016/j.bmcl.2013.06.055. Epub 2013 Jun 24.

Authors

Anthony R Gangloff¹, Jason Brown, Ron de Jong, Douglas R Dougan, Charles E Grimshaw, Mark Hixon, Andy Jennings, Ruhi Kamran, Andre Kiryanov, Shawn O'Connell, Ewan Taylor, Phong Vu

Affiliation

¹ Takeda California, 10410 Science Center Dr, San Diego, CA 92121, USA. anthony.gangloff@takeda.com

PMID: 23850199
DOI: 10.1016/j.bmcl.2013.06.055

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.

Keywords: 1,4-Benzoxazin-3-one; Chemopotentiation; PARP-1; Poly(ADP-ribose)polymerase inhibitors; Structure-based drug design.

MeSH terms

Animals
Benzoxazines / chemistry*
Benzoxazines / pharmacology*
Cell Line, Tumor
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Mice
Mice, Nude
Molecular Structure
Poly(ADP-ribose) Polymerase Inhibitors*

Substances

Benzoxazines
Enzyme Inhibitors
Poly(ADP-ribose) Polymerase Inhibitors