RGD Reference Report - Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation. - Rat Genome Database

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Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation.

Authors: Lorrain, DS  Bain, G  Correa, LD  Chapman, C  Broadhead, AR  Santini, AM  Prodanovich, PP  Darlington, JV  Stock, NS  Zunic, J  King, CD  Lee, C  Baccei, CS  Stearns, B  Roppe, J  Hutchinson, JH  Prasit, P  Evans, JF 
Citation: Lorrain DS, etal., Eur J Pharmacol. 2010 Aug 25;640(1-3):211-8. Epub 2010 May 21.
RGD ID: 5147468
Pubmed: PMID:20519143   (View Abstract at PubMed)
DOI: DOI:10.1016/j.ejphar.2010.05.003   (Journal Full-text)

We evaluated the in vivo pharmacological properties of AM803 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-p yridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, a selective five-lipoxygenase-activating protein (FLAP) inhibitor, using rat and mouse models of acute inflammation. Oral administration of AM803 (1 mg/kg) resulted in sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with >90% inhibition for up to 12 h and an EC50 of approximately 7 nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50s of 0.12 mg/kg and 0.37 mg/kg, respectively. The inhibition measured 16 h following a single oral dose of 3 mg/kg was 86% and 41% for LTB4 and CysLTs, respectively. In an acute inflammation setting, AM803 dose-dependently reduced LTB4, CysLTs, plasma protein extravasation and neutrophil influx induced by peritoneal zymosan injection. Finally, AM803 increased survival time in mice exposed to a lethal intravenous injection of platelet activating factor (PAF). The magnitude of effect was similar to that of an inhibitor of five-lipoxygenase (5-LO) and LTA4 hydrolase but superior to a leukotriene CysLT1 receptor antagonist. In summary, AM803 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute inflammation and in a model of lethal shock.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Alox5apRatpositive regulation of acute inflammatory response  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Alox5ap  (arachidonate 5-lipoxygenase activating protein)


Additional Information