Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase

Bioorg Med Chem Lett. 2006 Feb 15;16(4):1040-4. doi: 10.1016/j.bmcl.2005.10.081. Epub 2005 Nov 15.

Abstract

We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models.

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Phthalazines / chemical synthesis*
  • Phthalazines / chemistry
  • Phthalazines / pharmacology*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Phthalazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1