2. Academic Validation
  3. 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

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.
Thomas D Penning 1,  Gui-Dong Zhu,  Viraj B Gandhi,  Jianchun Gong,  Xuesong Liu,  Yan Shi,  Vered Klinghofer,  Eric F Johnson,  Cherrie K Donawho,  David J Frost,  Velitchka Bontcheva-Diaz,  Jennifer J Bouska,  Donald J Osterling,  Amanda M Olson,  Kennan C Marsh,  Yan Luo,  Vincent L Giranda
Affiliations

Affiliation

  • 1 Cancer Research, Pharmacokinetics, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. thomas.penning@abbott.com
PMID: 19143569 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.

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