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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
2008-9-19
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pubmed:abstractText |
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.
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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 |
Sep
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AimoneLisa DLD,
pubmed-author:AlmoSteven CSC,
pubmed-author:AngelesThelma STS,
pubmed-author:AtorMark AMA,
pubmed-author:Bozyczko-CoyneDonnaD,
pubmed-author:DieboldJames LJL,
pubmed-author:DurkinJohn TJT,
pubmed-author:FedorovAlexander AAA,
pubmed-author:FedorovElena VEV,
pubmed-author:HolskinBeverly PBP,
pubmed-author:HudkinsRobert LRL,
pubmed-author:HustenJeanJ,
pubmed-author:JosefKurt AKA,
pubmed-author:MallamoJohn PJP,
pubmed-author:MathiasenJoanne RJR,
pubmed-author:MeyerSheryl LSL,
pubmed-author:MurkJ LJL,
pubmed-author:ParkChung HoCH,
pubmed-author:SaporitoMichael SMS,
pubmed-author:ScottRichard WRW
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pubmed:issnType |
Electronic
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pubmed:day |
25
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5680-9
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:18714982-Administration, Oral,
pubmed-meshheading:18714982-Animals,
pubmed-meshheading:18714982-Carbazoles,
pubmed-meshheading:18714982-Cell Line, Tumor,
pubmed-meshheading:18714982-Crystallography, X-Ray,
pubmed-meshheading:18714982-Humans,
pubmed-meshheading:18714982-MAP Kinase Kinase Kinases,
pubmed-meshheading:18714982-Magnetic Resonance Spectroscopy,
pubmed-meshheading:18714982-Mice,
pubmed-meshheading:18714982-Models, Molecular,
pubmed-meshheading:18714982-Molecular Structure,
pubmed-meshheading:18714982-Protein Kinase Inhibitors,
pubmed-meshheading:18714982-Pyrrolidinones,
pubmed-meshheading:18714982-Rats
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pubmed:year |
2008
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pubmed:articleTitle |
Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.
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pubmed:affiliation |
Discovery Research, Cephalon, Incorporated, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. rhudkins@cephalon.com
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pubmed:publicationType |
Journal Article,
In Vitro
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