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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
24
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pubmed:dateCreated |
2010-12-17
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pubmed:abstractText |
A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC?? values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.
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pubmed:grant |
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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 |
Dec
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AherneWynneW,
pubmed-author:BawdenLindsayL,
pubmed-author:BelfieldAndrewA,
pubmed-author:BoneElisabethE,
pubmed-author:BrothertonDeborahD,
pubmed-author:ClarkVanessaV,
pubmed-author:DayFrancescaF,
pubmed-author:DonaldAlastairA,
pubmed-author:EcclesSuzanneS,
pubmed-author:HIRTH AHA,
pubmed-author:HardcastleAntheaA,
pubmed-author:MethR FRF,
pubmed-author:MoffatDavidD,
pubmed-author:MortensonPaulP,
pubmed-author:PatelSanjayS,
pubmed-author:RaynaudFlorenceF,
pubmed-author:RowlandsMartinM,
pubmed-author:StimsonLindsayL,
pubmed-author:WibawaJudataJ,
pubmed-author:van MeursSandraS
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pubmed:issnType |
Electronic
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pubmed:day |
23
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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 |
8663-78
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pubmed:meshHeading |
pubmed-meshheading:21080647-Animals,
pubmed-meshheading:21080647-Antineoplastic Agents,
pubmed-meshheading:21080647-Azabicyclo Compounds,
pubmed-meshheading:21080647-Cell Line, Tumor,
pubmed-meshheading:21080647-Dogs,
pubmed-meshheading:21080647-Drug Screening Assays, Antitumor,
pubmed-meshheading:21080647-Drug Synergism,
pubmed-meshheading:21080647-Female,
pubmed-meshheading:21080647-Histone Deacetylase Inhibitors,
pubmed-meshheading:21080647-Humans,
pubmed-meshheading:21080647-Mice,
pubmed-meshheading:21080647-Mice, Nude,
pubmed-meshheading:21080647-Microsomes, Liver,
pubmed-meshheading:21080647-Models, Molecular,
pubmed-meshheading:21080647-Neoplasm Transplantation,
pubmed-meshheading:21080647-Pyrimidines,
pubmed-meshheading:21080647-Rats,
pubmed-meshheading:21080647-Stereoisomerism,
pubmed-meshheading:21080647-Structure-Activity Relationship,
pubmed-meshheading:21080647-Tissue Distribution,
pubmed-meshheading:21080647-Transplantation, Heterologous
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pubmed:year |
2010
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pubmed:articleTitle |
Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor.
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pubmed:affiliation |
Chroma Therapeutics Ltd., Abingdon, OX14 4RY, UK. david.moffat@chromatherapeutics.com
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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