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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 |
2010-9-16
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pubmed:databankReference |
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pubmed:abstractText |
The discovery and characterization of 7k (BMS-582949), a highly selective p38? MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38? inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38? enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38? was confirmed by X-ray crystallographic analysis.
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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:BarrishJoel CJC,
pubmed-author:DoddJohn HJH,
pubmed-author:DoweykoArthur MAM,
pubmed-author:DyckmanAlaric JAJ,
pubmed-author:GilloolyKathleen MKM,
pubmed-author:HynesJohnJ,
pubmed-author:KieferSusan ESE,
pubmed-author:KishKevin FKF,
pubmed-author:LeftherisKaterinaK,
pubmed-author:LiTianleT,
pubmed-author:LinJamesJ,
pubmed-author:LinShuqunS,
pubmed-author:LiuChunjianC,
pubmed-author:MarathePunit HPH,
pubmed-author:McIntyreKim WKW,
pubmed-author:McKinnonMurrayM,
pubmed-author:NewittJohn AJA,
pubmed-author:PittSidneyS,
pubmed-author:SackJohn SJS,
pubmed-author:Salter-CidLuisaL,
pubmed-author:SchievenGary LGL,
pubmed-author:ShenDing RenDR,
pubmed-author:ShusterDavid JDJ,
pubmed-author:WityakJohnJ,
pubmed-author:WrobleskiStephen TST,
pubmed-author:WuHongH,
pubmed-author:ZhangHongjianH,
pubmed-author:ZhangRosemary FRF
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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 |
6629-39
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pubmed:meshHeading |
pubmed-meshheading:20804198-Animals,
pubmed-meshheading:20804198-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:20804198-Arthritis, Experimental,
pubmed-meshheading:20804198-Arthritis, Rheumatoid,
pubmed-meshheading:20804198-Biological Availability,
pubmed-meshheading:20804198-Caco-2 Cells,
pubmed-meshheading:20804198-Crystallography, X-Ray,
pubmed-meshheading:20804198-Female,
pubmed-meshheading:20804198-Humans,
pubmed-meshheading:20804198-Hydrogen Bonding,
pubmed-meshheading:20804198-Inflammation,
pubmed-meshheading:20804198-Lipopolysaccharides,
pubmed-meshheading:20804198-Male,
pubmed-meshheading:20804198-Mice,
pubmed-meshheading:20804198-Mice, Inbred BALB C,
pubmed-meshheading:20804198-Microsomes, Liver,
pubmed-meshheading:20804198-Mitogen-Activated Protein Kinase 14,
pubmed-meshheading:20804198-Models, Molecular,
pubmed-meshheading:20804198-Molecular Conformation,
pubmed-meshheading:20804198-Protein Binding,
pubmed-meshheading:20804198-Pyrroles,
pubmed-meshheading:20804198-Rats,
pubmed-meshheading:20804198-Rats, Inbred Lew,
pubmed-meshheading:20804198-Rats, Sprague-Dawley,
pubmed-meshheading:20804198-Stereoisomerism,
pubmed-meshheading:20804198-Structure-Activity Relationship,
pubmed-meshheading:20804198-Triazines,
pubmed-meshheading:20804198-Tumor Necrosis Factor-alpha
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pubmed:year |
2010
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pubmed:articleTitle |
Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38? MAP kinase inhibitor for the treatment of inflammatory diseases.
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pubmed:affiliation |
Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. chunjian.liu@bms.com
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pubmed:publicationType |
Journal Article,
In Vitro
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