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.

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.
Authors	Thomas D Penning, 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
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 2 Pg. 514-23 (Jan 22 2009) ISSN: 1520-4804 [Electronic] United States
PMID	19143569 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents Benzimidazoles Enzyme Inhibitors Poly(ADP-ribose) Polymerase Inhibitors veliparib Dacarbazine Cyclophosphamide Carboplatin Temozolomide
Topics	Animals Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology) Area Under Curve Benzimidazoles (administration & dosage, pharmacokinetics, pharmacology) Biological Availability Carboplatin (administration & dosage) Cyclophosphamide (administration & dosage) Dacarbazine (administration & dosage, analogs & derivatives) Dogs Enzyme Inhibitors (administration & dosage, pharmacokinetics, pharmacology) Female Haplorhini Humans Magnetic Resonance Spectroscopy Melanoma, Experimental (pathology) Mice Mice, SCID Poly(ADP-ribose) Polymerase Inhibitors Rats Temozolomide

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