title: Characterization of CGS 8515 as a selective 5-lipoxygenase inhibitor using in vitro and in vivo models.
abstract: CGS 8515 inhibited 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 synthesis in guinea pig leukocytes (IC50 = 0.1 microM). The compound did not appreciably affect cyclooxygenase (sheep seminal vesicles), 12-lipoxygenase (human platelets), 15-lipoxygenase (human leukocytes) and thromboxane synthetase (human platelets) at concentrations up to 100 microM. CGS 8515 inhibited A23187-induced formation of leukotriene products in whole blood (IC50 values of 0.8 and 4 microM, respectively, for human and rat) and in isolated rat lung (IC50 less than 1 microM) in vitro. The selectivity of the compound as a 5-lipoxygenase inhibitor was confirmed in rat whole blood by the 20-70-fold separation of inhibitory effects on the formation of leukotriene from prostaglandin products. Ex vivo and in vivo studies with rats showed that CGS 8515, at an oral dose of 2-50 mg/kg, significantly inhibited A23187-induced production of leukotrienes in whole blood and in the lung. The effect persisted for at least 6 h in the ex vivo whole blood model. CGS 8515, at oral doses as low as 5 mg/kg, significantly suppressed exudate volume and leukocyte migration in the carrageenan-induced pleurisy and sponge models in the rat. Inhibitory effects of the compound on inflammatory responses and leukotriene production in leukocytes and target organs are important parameters suggestive of its therapeutic potential in asthma, psoriasis and inflammatory conditions.
authors.affiliation: Research Department, Ciba-Geigy Corporation Summit, NJ 07901.
authors.forename: E C
authors.initials: EC
authors.lastname: Ku
authors.forename: A
authors.initials: A
authors.lastname: Raychaudhuri
authors.forename: G
authors.initials: G
authors.lastname: Ghai
authors.forename: E F
authors.initials: EF
authors.lastname: Kimble
authors.forename: W H
authors.initials: WH
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Colombo
authors.forename: R
authors.initials: R
authors.lastname: Dotson
authors.forename: T D
authors.initials: TD
authors.lastname: Oglesby
authors.forename: J W
authors.initials: JW
authors.lastname: Wasley
mesh_terms: D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D016227:Benzoquinones; D001711:Biotransformation; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007213:Indomethacin / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D010998:Pleurisy / Q000201:enzymology; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012756:Sheep; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D001095:Arachidonic Acids; D016227:Benzoquinones; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D011809:Quinones; D062367:ortho-Aminobenzoates; C055523:methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D003907:Dexamethasone; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001091:Arachidonate Lipoxygenases; D007213:Indomethacin