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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2009-1-15
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:Bontcheva-DiazVelitchkaV,
pubmed-author:BouskaJennifer JJJ,
pubmed-author:ChuI YIY,
pubmed-author:DonawhoCherrie KCK,
pubmed-author:FrostDavid JDJ,
pubmed-author:GandhiViraj BVB,
pubmed-author:GirandaVincent LVL,
pubmed-author:GongJianchunJ,
pubmed-author:JohnsonEric FEF,
pubmed-author:KlinghoferVeredV,
pubmed-author:LiuXuesongX,
pubmed-author:LuoYanY,
pubmed-author:MarshKennan CKC,
pubmed-author:OlsonAmanda MAM,
pubmed-author:OsterlingDonald JDJ,
pubmed-author:PenningThomas DTD,
pubmed-author:ZhuGui-DongGD
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pubmed:issnType |
Electronic
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pubmed:day |
22
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
514-23
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pubmed:meshHeading |
pubmed-meshheading:19143569-Animals,
pubmed-meshheading:19143569-Antineoplastic Agents,
pubmed-meshheading:19143569-Area Under Curve,
pubmed-meshheading:19143569-Benzimidazoles,
pubmed-meshheading:19143569-Biological Availability,
pubmed-meshheading:19143569-Carboplatin,
pubmed-meshheading:19143569-Cyclophosphamide,
pubmed-meshheading:19143569-Dacarbazine,
pubmed-meshheading:19143569-Dogs,
pubmed-meshheading:19143569-Enzyme Inhibitors,
pubmed-meshheading:19143569-Female,
pubmed-meshheading:19143569-Haplorhini,
pubmed-meshheading:19143569-Humans,
pubmed-meshheading:19143569-Magnetic Resonance Spectroscopy,
pubmed-meshheading:19143569-Melanoma, Experimental,
pubmed-meshheading:19143569-Mice,
pubmed-meshheading:19143569-Mice, SCID,
pubmed-meshheading:19143569-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:19143569-Rats
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pubmed:year |
2009
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pubmed:articleTitle |
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.
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pubmed:affiliation |
Cancer Research, Pharmacokinetics, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. thomas.penning@abbott.com
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pubmed:publicationType |
Journal Article
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