title: In-vitro versus in-vivo activities of new 5-lipoxygenase inhibitors with antiinflammatory activity.
abstract: The possible relationship between in-vitro inhibition of lipoxygenase (LO)/cyclooxygenase (CO) and in-vivo antiinflammatory effects of compounds such as isoflavanes (Zy 16369, Zy 16372, Zy 16681) was investigated. The latter were all shown to be potent 5-LO inhibitors when tested in vitro on human peritoneal macrophages (IC50 = 1-7 mumol/l). Zy 16372 and Zy 16681 also inhibited the 12- and 15-LO and, to a minor extent, the CO. In order to evaluate the antiinflammatory and antiproliferative effects of these compounds in vivo they were applied topically to mice. No definite correlation could be made between the inhibition of the ear oedema induced by arachidonic acid (AA), the inhibition of the epidermal ornithine-decarboxylase (ODC) activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), and the in-vitro activities of the compounds. Zy 16372 appeared to inhibit the oedema dose-dependently (ED50 = 5 mumol/ear) and seemed to be the most potent among the 3 compounds tested and slightly more potent than the reference compound nordihydroguaiaretic acid. As inhibitors of TPA-induced ODC, all 3 compounds exhibited comparable activity. These results suggest that the in-vivo effects of the compounds might be mediated by components other than AA metabolites, and/or be related to their specific kinetic patterns.
authors.affiliation: Zyma SA, Nyon, Switzerland.
authors.forename: J B
authors.initials: JB
authors.lastname: Montandon
authors.forename: F J
authors.initials: FJ
authors.lastname: Zijlstra
authors.forename: J H
authors.initials: JH
authors.lastname: Wilson
authors.forename: E M
authors.initials: EM
authors.lastname: Grandjean
authors.forename: L
authors.initials: L
authors.lastname: Cicurel
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D002455:Cell Division / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids / Q000096:biosynthesis; D004817:Epidermis / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009955:Ornithine Decarboxylase / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D005419:Flavonoids; D007529:Isoflavones; D016859:Lipoxygenase Inhibitors; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate