title: CJ-13610, an orally active inhibitor of 5-lipoxygenase is efficacious in preclinical models of pain.
abstract: Zileuton, a redox and iron chelator 5-lipoxygenase (5-LOX) inhibitor and, leukotriene receptor antagonists are presently used clinically in the long term treatment of asthma. Recent data implicate 5-LOX pathway in pain signaling. We report 5-LOX expression in the central nervous system (CNS) and analyze the pain efficacy of a new class of non redox, non iron chelating 5-LOX inhibitor. CJ-13610, 4-(3-(4-(2-methyl-1H-imidazol-1-yl) phenylthio) phenyl)-tetrahydro-2H-pyran-4-carboxamide, demonstrated antihyperalgesic activity in inflammatory pain models including the acute carrageenan model and the chronic inflammatory model using complete Freund's adjuvant. Following complete Freund's adjuvant stimulus leukotrieneB(4) concentration in the brain was elevated (9+/-1 ng/g, mean+/-S.E.M.) by about 3 times that of the control group (3+/-0.11, mean+/-S.E.M.). Hyperalgesia and leukotrieneB(4) concentration were both reversed following CJ-13610 treatment. Furthermore, we demonstrate CJ-13610 efficacy against osteoarthritis like pain using the rat medial meniscal transection model. CJ-13610 at oral doses of 0.6, 2 and 6 mg/kg/day reversed two modalities of pain in this model; tactile allodynia and weight bearing differential. Taken together, these data suggest that 5-LOX pathway and the leukotriene products are important mediators of pain.
authors: Pfizer Global Research & Development, St Louis Laboratories, Pfizer Inc, St Louis, MO 63017, USA. luz.a.cortes-burgos@pfizer.com
authors: Luz A
authors: LA
authors: Cortes-Burgos
authors: Ben S
authors: BS
authors: Zweifel
authors: Steven L
authors: SL
authors: Settle
authors: Robert A
authors: RA
authors: Pufahl
authors: Gary D
authors: GD
authors: Anderson
authors: Medora M
authors: MM
authors: Hardy
authors: Dana E
authors: DE
authors: Weir
authors: George
authors: G
authors: Hu
authors: Fernando A
authors: FA
authors: Happa
authors: Zachary
authors: Z
authors: Stewart
authors: Shanmugam
authors: S
authors: Muthian
authors: Matthew J
authors: MJ
authors: Graneto
authors: Jaime L
authors: JL
authors: Masferrer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D005620:Freund's Adjuvant / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D010003:Osteoarthritis / Q000150:complications; D010146:Pain / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013440:Sulfides / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C496810:CJ 13610; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013440:Sulfides; D005620:Freund's Adjuvant; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea