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

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

  • Eur J Pharmacol. 2010 Aug 25;640(1-3):211-8. doi: 10.1016/j.ejphar.2010.05.003.
Daniel S Lorrain 1 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
Affiliations

Affiliation

  • 1 Amira Pharmaceuticals, 9535 Waples Street, Ste. 100, San Diego, California 92121, USA. dan.lorrain@amirapharm.com
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.

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