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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2010-4-15
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pubmed:abstractText |
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.
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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 |
Apr
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:Bontcheva-DiazVelitchkaV,
pubmed-author:BouskaJennifer JJJ,
pubmed-author:BuchananFritz GFG,
pubmed-author:BukofzerGail TGT,
pubmed-author:ChuI YIY,
pubmed-author:DonawhoCherrie KCK,
pubmed-author:FrostDavid JDJ,
pubmed-author:FryElizabeth HEH,
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:ParkChang HCH,
pubmed-author:PenningThomas DTD,
pubmed-author:RodriguezLuis ELE,
pubmed-author:ThomasSheelaS,
pubmed-author:ZhuGui-DongGD
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pubmed:issnType |
Electronic
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pubmed:day |
22
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3142-53
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pubmed:meshHeading |
pubmed-meshheading:20337371-Animals,
pubmed-meshheading:20337371-Antineoplastic Agents,
pubmed-meshheading:20337371-Antineoplastic Combined Chemotherapy Protocols,
pubmed-meshheading:20337371-BRCA1 Protein,
pubmed-meshheading:20337371-Benzimidazoles,
pubmed-meshheading:20337371-Biological Availability,
pubmed-meshheading:20337371-Blood-Brain Barrier,
pubmed-meshheading:20337371-Carboplatin,
pubmed-meshheading:20337371-Cell Line, Tumor,
pubmed-meshheading:20337371-Crystallography, X-Ray,
pubmed-meshheading:20337371-Dacarbazine,
pubmed-meshheading:20337371-Drug Screening Assays, Antitumor,
pubmed-meshheading:20337371-Female,
pubmed-meshheading:20337371-Melanoma, Experimental,
pubmed-meshheading:20337371-Mice,
pubmed-meshheading:20337371-Mice, Inbred C57BL,
pubmed-meshheading:20337371-Mice, SCID,
pubmed-meshheading:20337371-Models, Molecular,
pubmed-meshheading:20337371-Neoplasm Transplantation,
pubmed-meshheading:20337371-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:20337371-Stereoisomerism,
pubmed-meshheading:20337371-Structure-Activity Relationship,
pubmed-meshheading:20337371-Transplantation, Heterologous
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pubmed:year |
2010
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pubmed:articleTitle |
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.
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pubmed:affiliation |
Cancer Research, 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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