title: Synthesis and biological evaluation of 1,2,4-triazinylphenylalkylthiazolecarboxylic acid esters as cytokine-inhibiting antedrugs with strong bronchodilating effects in an animal model of asthma.
abstract: The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkylthiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC(50) = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC(50) = 220 nM), MCP-2 (IC(50) = 580 nM), and MCP-3 (IC(50) = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol.
authors.affiliation: Medicinal Chemistry Department and Department of Inflammation, Johnson & Johnson Pharmaceutical Research and Development, a Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Eddy J
authors.initials: EJ
authors.lastname: Freyne
authors.forename: Jean F
authors.initials: JF
authors.lastname: Lacrampe
authors.forename: Frederik
authors.initials: F
authors.lastname: Deroose
authors.forename: Gustaaf M
authors.initials: GM
authors.lastname: Boeckx
authors.forename: Marc
authors.initials: M
authors.lastname: Willems
authors.forename: Werner
authors.initials: W
authors.lastname: Embrechts
authors.forename: Erwin
authors.initials: E
authors.lastname: Coesemans
authors.forename: Johan J
authors.initials: JJ
authors.lastname: Willems
authors.forename: Jerome M
authors.initials: JM
authors.lastname: Fortin
authors.forename: Yannick
authors.initials: Y
authors.lastname: Ligney
authors.forename: Lieve L
authors.initials: LL
authors.lastname: Dillen
authors.forename: Willy F
authors.initials: WF
authors.lastname: Cools
authors.forename: Jan
authors.initials: J
authors.lastname: Goossens
authors.forename: David
authors.initials: D
authors.lastname: Corens
authors.forename: Alex
authors.initials: A
authors.lastname: De Groot
authors.forename: Jean P
authors.initials: JP
authors.lastname: Van Wauwe
mesh_terms: D000328:Adult; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004952:Esters / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012756:Sheep; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C500083:3-hydroxypropyl 2-(1-(2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl)-1-methylethyl)-4-phenyl-5-thiazolecarboxylate; D001993:Bronchodilator Agents; C111835:CCL2 protein, human; C515450:CCL7 protein, human; C515453:CCL8 protein, human; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D016207:Cytokines; D004952:Esters; D015848:Interleukin-5; D016209:Interleukin-8; D018945:Monocyte Chemoattractant Proteins; D013844:Thiazoles; D014227:Triazines; D015847:Interleukin-4