Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1094-9. doi: 10.1016/j.bmcl.2009.12.026. Epub 2009 Dec 6.

Abstract

Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • BRCA1 Protein / deficiency
  • BRCA1 Protein / metabolism
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • HeLa Cells
  • Humans
  • Indolizines / chemistry
  • Indolizines / metabolism
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Binding / physiology
  • Pyrazines / chemistry*
  • Pyrazines / metabolism*
  • Rats
  • Structure-Activity Relationship

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Indolizines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyrazines
  • indolizine
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases