Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer

J Med Chem. 2009 Jan 22;52(2):514-23. doi: 10.1021/jm801171j.

Abstract

We have developed a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors with a methyl-substituted quaternary center at the point of attachment to the benzimidazole ring system. These compounds exhibit excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a K(i) of 5 nM and in a C41 whole cell assay with an EC(50) of 2 nM. In addition, 3a 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 cancer xenograft model in combination with either carboplatin or cyclophosphamide.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Area Under Curve
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Biological Availability
  • Carboplatin / administration & dosage
  • Cyclophosphamide / administration & dosage
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives
  • Dogs
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Haplorhini
  • Humans
  • Magnetic Resonance Spectroscopy
  • Melanoma, Experimental / pathology*
  • Mice
  • Mice, SCID
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Rats
  • Temozolomide

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • veliparib
  • Dacarbazine
  • Cyclophosphamide
  • Carboplatin
  • Temozolomide