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

• Published in: European journal of pharmacology 2010-08, Vol.640 (1), p.211-218
• Main Authors: Lorrain, Daniel S., Bain, Gretchen, Correa, Lucia D., Chapman, Charles, Broadhead, Alex R., Santini, Angelina M., Prodanovich, Patricia P., Darlington, Janice V., Stock, Nicholas S., Zunic, Jasmine, King, Christopher D., Lee, Catherine, Baccei, Christopher S., Stearns, Brian, Roppe, Jeffrey, Hutchinson, John H., Prasit, Peppi, Evans, Jilly F.
• Format: Article
• Language: English
• Subjects: 5-lipoxygenase; 5-Lipoxygenase-Activating Proteins; Animals; Asthma; Biological and medical sciences; Carrier Proteins - antagonists & inhibitors; Chronic Disease; Chronic obstructive pulmonary disease, asthma; Cysteine - biosynthesis; Cysteinyl leukotriene; Disease Models, Animal; Female; FLAP; Humans; Indoles - pharmacokinetics; Indoles - pharmacology; Indoles - therapeutic use; Inflammation - drug therapy; Inflammation - metabolism; Leukotriene; Leukotriene B4 - biosynthesis; Leukotrienes - biosynthesis; LTB 4; Lung - drug effects; Lung - metabolism; Male; Medical sciences; Membrane Proteins - antagonists & inhibitors; Mice; Pentanoic Acids - pharmacokinetics; Pentanoic Acids - pharmacology; Pentanoic Acids - therapeutic use; Pharmacology. Drug treatments; Platelet Activating Factor - pharmacology; Pneumology; Propionates - pharmacokinetics; Propionates - pharmacology; Propionates - therapeutic use; Rats; Substrate Specificity; Zymosan - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2010.05.003

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)-1 H-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 LTB 4 biosynthesis with > 90% inhibition for up to 12 h and an EC 50 of ∼ 7 nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB 4 and cysteinyl leukotriene (CysLT) production with ED 50s 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 LTB 4 and CysLTs, respectively. In an acute inflammation setting, AM803 dose-dependently reduced LTB 4, 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 LTA 4 hydrolase but superior to a leukotriene CysLT 1 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.