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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
2009-11-20
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pubmed:abstractText |
We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
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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 |
Nov
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AltamuraSergioS,
pubmed-author:BoueresJuliaJ,
pubmed-author:FerrignoFedericaF,
pubmed-author:FonsiMassimilianoM,
pubmed-author:GiominiClaudiaC,
pubmed-author:JonesPhilipP,
pubmed-author:LamartinaStefaniaS,
pubmed-author:MonteagudoEdithE,
pubmed-author:OntoriaJesus MJM,
pubmed-author:OrsaleMaria VittoriaMV,
pubmed-author:PalumbiMaria CeciliaMC,
pubmed-author:PesciSilviaS,
pubmed-author:RoscilliGiuseppeG,
pubmed-author:RowleyMichaelM,
pubmed-author:ScarpelliRitaR,
pubmed-author:Schultz-FademrechtCarstenC,
pubmed-author:ToniattiCarloC
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pubmed:issnType |
Electronic
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pubmed:day |
26
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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 |
7170-85
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pubmed:meshHeading |
pubmed-meshheading:19873981-Administration, Oral,
pubmed-meshheading:19873981-Amides,
pubmed-meshheading:19873981-Animals,
pubmed-meshheading:19873981-Cell Line, Tumor,
pubmed-meshheading:19873981-Cell Proliferation,
pubmed-meshheading:19873981-Cell Transformation, Neoplastic,
pubmed-meshheading:19873981-Drug Discovery,
pubmed-meshheading:19873981-Drug Stability,
pubmed-meshheading:19873981-Enzyme Inhibitors,
pubmed-meshheading:19873981-Female,
pubmed-meshheading:19873981-Genes, BRCA1,
pubmed-meshheading:19873981-Genes, BRCA2,
pubmed-meshheading:19873981-Humans,
pubmed-meshheading:19873981-Indazoles,
pubmed-meshheading:19873981-Inhibitory Concentration 50,
pubmed-meshheading:19873981-Mutation,
pubmed-meshheading:19873981-Neoplasms,
pubmed-meshheading:19873981-Piperidines,
pubmed-meshheading:19873981-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:19873981-Rats
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pubmed:year |
2009
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pubmed:articleTitle |
Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
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pubmed:affiliation |
IRBM/Merck Research Labs Rome, Via Pontina km 30,600, 00040 Pomezia, Italy. philip_jones@merck.com
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pubmed:publicationType |
Journal Article
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