Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors

Bioorg Med Chem Lett. 2010 Jan 15;20(2):488-92. doi: 10.1016/j.bmcl.2009.11.127. Epub 2009 Dec 1.

Abstract

A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which displayed excellent PARP enzyme inhibition with IC(50)=4nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC(50)=42nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Azetidines / chemical synthesis*
  • Azetidines / chemistry
  • Azetidines / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Humans
  • Indazoles / chemical synthesis*
  • Indazoles / chemistry
  • Indazoles / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rats
  • Structure-Activity Relationship
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Amides
  • Antineoplastic Agents
  • Azetidines
  • Enzyme Inhibitors
  • Indazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • BRAP protein, human
  • Ubiquitin-Protein Ligases
  • Poly(ADP-ribose) Polymerases