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

Abstract

We evaluated the in vivo pharmacological properties of AM803 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-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.

• Authors: Daniel S Lorrain, Gretchen Bain, Lucia D Correa, Charles Chapman, Alex R Broadhead, Angelina M Santini, Patricia P Prodanovich, Janice V Darlington, Nicholas S Stock, Jasmine Zunic, Christopher D King, Catherine Lee, Christopher S Baccei, Brian Stearns, Jeffrey Roppe, John H Hutchinson, Peppi Prasit, Jilly F Evans
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 640 Issue 1-3 Pg. 211-8 (Aug 25 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20519143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier B.V. All rights reserved.

Chemical References

• 3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid
• 5-Lipoxygenase-Activating Proteins
• ALOX5AP protein, human
• Alox5ap protein, mouse
• Alox5ap protein, rat
• Carrier Proteins
• Indoles
• Leukotrienes
• Membrane Proteins
• Pentanoic Acids
• Platelet Activating Factor
• Propionates
• cysteinyl-leukotriene
• Leukotriene B4
• Zymosan
• propionic acid
• Cysteine

Topics

• 5-Lipoxygenase-Activating Proteins
• Animals
• Carrier Proteins (antagonists & inhibitors)
• Chronic Disease
• Cysteine (biosynthesis)
• Disease Models, Animal
• Female
• Humans
• Indoles (pharmacokinetics, pharmacology, therapeutic use)
• Inflammation (drug therapy, metabolism)
• Leukotriene B4 (biosynthesis)
• Leukotrienes (biosynthesis)
• Lung (drug effects, metabolism)
• Male
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Pentanoic Acids (pharmacokinetics, pharmacology, therapeutic use)
• Platelet Activating Factor (pharmacology)
• Propionates (pharmacokinetics, pharmacology, therapeutic use)
• Rats
• Substrate Specificity
• Zymosan (pharmacology)