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 (AM103), a novel selective 5-lipoxygenase-activating protein inhibitor that reduces acute and chronic inflammation.

Abstract

Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) 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 LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), 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.

• Authors: Daniel S Lorrain, Gretchen Bain, Lucia D Correa, Charles Chapman, Alex R Broadhead, Angelina M Santini, Pat Prodanovich, Janice V Darlington, John H Hutchinson, Christopher King, Catherine Lee, Christopher Baccei, Yiwei Li, Jeannie M Arruda, Jilly F Evans
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 331 Issue 3 Pg. 1042-50 (Dec 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19749079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3-tert-butylsulfanyl-1-(4-(6-methoxypyridin-3-yl)benzyl)-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid
• 5-Lipoxygenase-Activating Proteins
• ALOX5AP protein, human
• Alox5ap protein, mouse
• Alox5ap protein, rat
• Anti-Inflammatory Agents, Non-Steroidal
• Carrier Proteins
• Indoles
• Membrane Proteins
• Propionates
• Leukotriene B4
• Zymosan

Topics

• 5-Lipoxygenase-Activating Proteins
• Acute Disease
• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Asthma (drug therapy, enzymology, metabolism)
• Carrier Proteins (antagonists & inhibitors)
• Chronic Disease
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Extravasation of Diagnostic and Therapeutic Materials (drug therapy, enzymology, metabolism)
• Female
• Humans
• Indoles (pharmacology, therapeutic use)
• Inflammation (drug therapy, enzymology, metabolism)
• Leukotriene B4 (biosynthesis, blood)
• Male
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Pneumonia (drug therapy, enzymology, metabolism)
• Propionates (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Zymosan