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

DS Lorrain, G Bain, LD Correa, C Chapman… - European journal of …, 2010 - Elsevier
DS Lorrain, G Bain, LD Correa, C Chapman, AR Broadhead, AM Santini, PP Prodanovich…
European journal of pharmacology, 2010Elsevier
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 (1mg/kg) resulted in
sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with>
90% inhibition for up to 12h and an EC50 of∼ 7nM. When rat lungs were challenged in vivo …
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 (1mg/kg) resulted in sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with >90% inhibition for up to 12h and an EC50 of ∼7nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50s of 0.12mg/kg and 0.37mg/kg, respectively. The inhibition measured 16h following a single oral dose of 3mg/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.
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