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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
12
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pubmed:dateCreated |
2008-6-19
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pubmed:abstractText |
The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
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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 |
Jun
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AbrahamWilliam MWM,
pubmed-author:BehnkeMark LML,
pubmed-author:ChenLihrenL,
pubmed-author:ClarkJames DJD,
pubmed-author:DonahueFrancesF,
pubmed-author:FoleyMegan AMA,
pubmed-author:GoodwinDebra GDG,
pubmed-author:HegenMartinM,
pubmed-author:HuBaihuaB,
pubmed-author:HuYonghanY,
pubmed-author:IpekManusM,
pubmed-author:JamesKeithK,
pubmed-author:KirincichSteven JSJ,
pubmed-author:KuM SherryMS,
pubmed-author:LeeKatherine LKL,
pubmed-author:LeoAlbertA,
pubmed-author:LiZ CZC,
pubmed-author:McKewJohn CJC,
pubmed-author:MichalakRonaldR,
pubmed-author:MurphyElizabeth AEA,
pubmed-author:Nickerson-NutterCheryl LCL,
pubmed-author:RamaraoManjunath KMK,
pubmed-author:ShenMarina W HMW,
pubmed-author:StentV CVC,
pubmed-author:SumFuk-WahFW,
pubmed-author:ThakkerPareshP,
pubmed-author:ThomasonJenniferJ,
pubmed-author:WilliamsCaraC,
pubmed-author:WooderLaneL,
pubmed-author:WuKunK
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pubmed:issnType |
Print
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pubmed:day |
26
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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 |
3388-413
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pubmed:meshHeading |
pubmed-meshheading:18498150-Animals,
pubmed-meshheading:18498150-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:18498150-Arthritis, Experimental,
pubmed-meshheading:18498150-Benzoic Acids,
pubmed-meshheading:18498150-Biological Availability,
pubmed-meshheading:18498150-Bronchoconstriction,
pubmed-meshheading:18498150-Calorimetry,
pubmed-meshheading:18498150-Carrageenan,
pubmed-meshheading:18498150-Cell Line,
pubmed-meshheading:18498150-Cyclooxygenase 2 Inhibitors,
pubmed-meshheading:18498150-Edema,
pubmed-meshheading:18498150-Group IV Phospholipases A2,
pubmed-meshheading:18498150-Humans,
pubmed-meshheading:18498150-Isoenzymes,
pubmed-meshheading:18498150-Male,
pubmed-meshheading:18498150-Mice,
pubmed-meshheading:18498150-Protein Binding,
pubmed-meshheading:18498150-Rats,
pubmed-meshheading:18498150-Rats, Sprague-Dawley,
pubmed-meshheading:18498150-Sheep,
pubmed-meshheading:18498150-Structure-Activity Relationship,
pubmed-meshheading:18498150-Sulfonamides
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pubmed:year |
2008
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pubmed:articleTitle |
Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib.
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pubmed:affiliation |
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. jmckew@wyeth.com
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pubmed:publicationType |
Journal Article,
In Vitro
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