Optimization of Phenyl-Substituted Benzimidazole Carboxamide poly(ADP-ribose) Polymerase Inhibitors: Identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a Highly Potent and Efficacious Inhibitor

J Med Chem. 2010 Apr 22;53(8):3142-53. doi: 10.1021/jm901775y.

Abstract

We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • BRCA1 Protein / deficiency
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use
  • Biological Availability
  • Blood-Brain Barrier / metabolism
  • Carboplatin / administration & dosage
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives
  • Drug Screening Assays, Antitumor
  • Female
  • Melanoma, Experimental / drug therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Models, Molecular
  • Neoplasm Transplantation
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Temozolomide
  • Transplantation, Heterologous

Substances

  • 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide
  • Antineoplastic Agents
  • BRCA1 Protein
  • Benzimidazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Dacarbazine
  • Carboplatin
  • Temozolomide