title: Pharmacology of PF-4191834, a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain.
abstract: 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 IC(50) = 229 +/- 20 nM. Furthermore, it demonstrated approximately 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 IC(80) = 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.
authors.affiliation: Inflammation Research Unit, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc., Chesterfield, Missouri, USA. Jaime.l.masferrer@pfizer.com
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Masferrer
authors.forename: Ben S
authors.initials: BS
authors.lastname: Zweifel
authors.forename: Medora
authors.initials: M
authors.lastname: Hardy
authors.forename: Gary D
authors.initials: GD
authors.lastname: Anderson
authors.forename: Dawn
authors.initials: D
authors.lastname: Dufield
authors.forename: Luz
authors.initials: L
authors.lastname: Cortes-Burgos
authors.forename: Robert A
authors.initials: RA
authors.lastname: Pufahl
authors.forename: Matthew
authors.initials: M
authors.lastname: Graneto
mesh_terms: D000818:Animals; D001249:Asthma / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D007962:Leukocytes / Q000201:enzymology; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D010146:Pain / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013053:Spectrophotometry; D013440:Sulfides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C550724:4-(3-(4-(1-methyl-1H-pyrazol-5-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013440:Sulfides; D007975:Leukotriene B4