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.
Anthony R Gangloff  1 ,  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
Affiliations
  • 1. Takeda California, 10410 Science Center Dr, San Diego, CA 92121, USA. [email protected]
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.