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rdf:type |
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lifeskim:mentions |
umls-concept:C0034242,
umls-concept:C0038477,
umls-concept:C0205531,
umls-concept:C0226896,
umls-concept:C0243077,
umls-concept:C0257535,
umls-concept:C0442027,
umls-concept:C0470187,
umls-concept:C1261322,
umls-concept:C1527415,
umls-concept:C1708111
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pubmed:issue |
16
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pubmed:dateCreated |
2009-7-29
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pubmed:abstractText |
A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.
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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 |
Aug
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pubmed:issn |
1464-3405
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pubmed:author |
pubmed-author:ChmaitSamerS,
pubmed-author:HenkleBradleyB,
pubmed-author:HsiehFayeF,
pubmed-author:LeeMatthew RMR,
pubmed-author:McBrideHelenH,
pubmed-author:MinerKentK,
pubmed-author:MohrChristopherC,
pubmed-author:PettusLiping HLH,
pubmed-author:PlantMatthewM,
pubmed-author:SarisChristiaan J MCJ,
pubmed-author:ShermanLisaL,
pubmed-author:TaskerAndrew SAS,
pubmed-author:WongLu MinLM,
pubmed-author:WurzRyan PRP,
pubmed-author:XuShiminS
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
19
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4724-8
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:19574047-Administration, Oral,
pubmed-meshheading:19574047-Animals,
pubmed-meshheading:19574047-Anti-Inflammatory Agents,
pubmed-meshheading:19574047-Binding Sites,
pubmed-meshheading:19574047-Cell Line,
pubmed-meshheading:19574047-Computer Simulation,
pubmed-meshheading:19574047-Crystallography, X-Ray,
pubmed-meshheading:19574047-Humans,
pubmed-meshheading:19574047-Interleukin-8,
pubmed-meshheading:19574047-Lipopolysaccharides,
pubmed-meshheading:19574047-Male,
pubmed-meshheading:19574047-Mitogen-Activated Protein Kinase 14,
pubmed-meshheading:19574047-Protein Kinase Inhibitors,
pubmed-meshheading:19574047-Pyrazoles,
pubmed-meshheading:19574047-Pyridones,
pubmed-meshheading:19574047-Rats,
pubmed-meshheading:19574047-Rats, Sprague-Dawley,
pubmed-meshheading:19574047-Structure-Activity Relationship,
pubmed-meshheading:19574047-Tumor Necrosis Factor-alpha
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pubmed:year |
2009
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pubmed:articleTitle |
Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.
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pubmed:affiliation |
Department of Chemistry Research & Discovery, Amgen Inc, Thousand Oaks, CA 91320, USA. rwurz@amgen.com
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pubmed:publicationType |
Journal Article
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