Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer

Bioorg Med Chem. 2008 Jul 15;16(14):6965-75. doi: 10.1016/j.bmc.2008.05.044. Epub 2008 May 27.


We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Cisplatin / therapeutic use
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / therapeutic use
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Melanoma, Experimental / drug therapy*
  • Mice
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Structure-Activity Relationship
  • Temozolomide
  • Transplantation, Heterologous
  • Xenograft Model Antitumor Assays


  • Benzimidazoles
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Dacarbazine
  • Cisplatin
  • Temozolomide