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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2007-2-15
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pubmed:abstractText |
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
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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 |
Feb
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AlbrechtBrian KBK,
pubmed-author:BellonSteveS,
pubmed-author:BreadyJamesJ,
pubmed-author:CaenepeelSeanS,
pubmed-author:CeeVictor JVJ,
pubmed-author:ChaffeeStuart CSC,
pubmed-author:CoxonAngelaA,
pubmed-author:EmeryMauriceM,
pubmed-author:FretlandJenneJ,
pubmed-author:GallantPaulP,
pubmed-author:Geuns-MeyerStephanie DSD,
pubmed-author:GuYanY,
pubmed-author:HodousBrian LBL,
pubmed-author:HoffmanDougD,
pubmed-author:HughesPaul EPE,
pubmed-author:JohnsonRebecca ERE,
pubmed-author:KendallRichardR,
pubmed-author:KimJoseph LJL,
pubmed-author:LongAlexander MAM,
pubmed-author:MorrisonMichaelM,
pubmed-author:OlivieriPhilip RPR,
pubmed-author:PatelVinod FVF,
pubmed-author:PolverinoAnthonyA,
pubmed-author:RosePaulP,
pubmed-author:TempestPaulP,
pubmed-author:WangLingL,
pubmed-author:WhittingtonDouglas ADA,
pubmed-author:ZhaoHuilinH
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pubmed:issnType |
Print
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pubmed:day |
22
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
611-26
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:17253678-Administration, Oral,
pubmed-meshheading:17253678-Angiogenesis Inhibitors,
pubmed-meshheading:17253678-Animals,
pubmed-meshheading:17253678-Benzamides,
pubmed-meshheading:17253678-Binding Sites,
pubmed-meshheading:17253678-Blood Proteins,
pubmed-meshheading:17253678-Crystallography, X-Ray,
pubmed-meshheading:17253678-Female,
pubmed-meshheading:17253678-Humans,
pubmed-meshheading:17253678-Injections, Intraperitoneal,
pubmed-meshheading:17253678-Injections, Intravenous,
pubmed-meshheading:17253678-Male,
pubmed-meshheading:17253678-Mice,
pubmed-meshheading:17253678-Models, Molecular,
pubmed-meshheading:17253678-Molecular Structure,
pubmed-meshheading:17253678-Phosphorylation,
pubmed-meshheading:17253678-Protein Binding,
pubmed-meshheading:17253678-Pyridines,
pubmed-meshheading:17253678-Rats,
pubmed-meshheading:17253678-Rats, Sprague-Dawley,
pubmed-meshheading:17253678-Receptor, TIE-2,
pubmed-meshheading:17253678-Structure-Activity Relationship,
pubmed-meshheading:17253678-Triazines,
pubmed-meshheading:17253678-Vascular Endothelial Growth Factor Receptor-2
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pubmed:year |
2007
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pubmed:articleTitle |
Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
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pubmed:affiliation |
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139-1581, USA. bhodous@amgen.com
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pubmed:publicationType |
Journal Article
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