PT - JOURNAL ARTICLE AU - Jaime L. Masferrer AU - Ben S. Zweifel AU - Medora Hardy AU - Gary D. Anderson AU - Dawn Dufield AU - Luz Cortes-Burgos AU - Robert A. Pufahl AU - Matthew Graneto TI - Pharmacology of PF-4191834, a Novel, Selective Non-Redox 5-Lipoxygenase Inhibitor Effective in Inflammation and Pain AID - 10.1124/jpet.110.166967 DP - 2010 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 294--301 VI - 334 IP - 1 4099 - http://jpet.aspetjournals.org/content/334/1/294.short 4100 - http://jpet.aspetjournals.org/content/334/1/294.full SO - J Pharmacol Exp Ther2010 Jul 01; 334 AB - 5-Lipoxygenase (LOX) is an important arachidonic acid-metabolizing enzyme producing leukotrienes and other proinflammatory lipid mediators with potent pathophysiological functions in asthma and other inflammatory diseases. 4-(3-(4-(1-Methyl-1H-pyrazol-5-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (PF-4191834) is a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. In vitro and in vivo assays were developed for the evaluation of a novel 5-LOX inhibitor using conditions of maximal enzyme activity. PF-4191834 exhibits good potency in enzyme- and cell-based assays, as well as in a rat model of acute inflammation. Enzyme assay results indicate that PF-4191834 is a potent 5-LOX inhibitor, with an IC50 = 229 ± 20 nM. Furthermore, it demonstrated ∼300-fold selectivity for 5-LOX over 12-LOX and 15-LOX and shows no activity toward the cyclooxygenase enzymes. In addition, PF-4191834 inhibits 5-LOX in human blood cells, with an IC80 = 370 ± 20 nM. This inhibitory concentration correlates well with plasma exposures needed for in vivo efficacy in inflammation in models of inflammatory pain. The combination of potency in cells and in vivo, together with a sustained in vivo effect, provides PF-4191834 with an overall pharmacodynamic improvement consistent with once a day dosing. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics