Pharmacological characterization of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2, 2-dimethyl-propionic acid …

DS Lorrain, G Bain, LD Correa, C Chapman… - … of Pharmacology and …, 2009 - ASPET
DS Lorrain, G Bain, LD Correa, C Chapman, AR Broadhead, AM Santini, P Prodanovich…
Journal of Pharmacology and Experimental Therapeutics, 2009ASPET
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of
arachidonic acid (AA) to LTA4 by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-
activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-
(pyridin-2-ylmethoxy)-1 H-indol-2-yl]-2, 2-dimethyl-propionic acid (AM103) is a novel
selective FLAP inhibitor in development for the treatment of respiratory conditions such as
asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB4 assay, AM103 …
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA4 by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB4 assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC50 of ∼60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50 values of 0.8 and 1 mg/kg, respectively. In this model, the EC50 derived from plasma AM103 was ∼330 nM for inhibition of both LTB4 and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB4, CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.
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