The 5-lipoxygenase inhibitors ZD2138 and ZM230487 are potent and selective inhibitors of several antigen-induced guinea-pig pulmonary responses

• Published in: European journal of pharmacology Vol. 257; no. 3; pp. 285 - 292
• Main Authors: Kusner, Edward J., Buckner, Carl K., Dea, Donna M., DeHaas, Christopher J., Marks, Rebecca L., Krell, Robert D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 23.05.1994; Elsevier
• Subjects: 5-Lipoxygenase; Airway Resistance - drug effects; Animals; Antigens - immunology; Biological and medical sciences; Cyclooxygenase Inhibitors - pharmacology; Guinea Pigs; Histamine and antagonists. Allergy; Histamine Release - drug effects; Indoles - pharmacology; Leukotriene; Leukotrienes - metabolism; Lipoxygenase Inhibitors - pharmacology; Lung - drug effects; Lung - immunology; Lung - metabolism; Male; Medical sciences; MK-886; Pharmacology. Drug treatments; Phospholipases A - antagonists & inhibitors; Phospholipases A2; Pyrans - pharmacology; Quinolones - pharmacology; Thromboxane B2 - metabolism; Thromboxane-A Synthase - antagonists & inhibitors; ZD2138; Zileuton; ZM230487; Leukotriene; MK-886; ZM230487; ZD2138; 5-Lipoxygenase; Zileuton; Immunopathology; Allergy; Enzyme; Respiratory disease; Rodentia; Enzyme inhibitor; Biological activity; Vertebrata; Mammalia; Guinea pig; Animal; Oxidoreductases; Lipoxygenase; Mechanism of action
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(94)90140-6

The non-redox 5-lipoxygenase inhibitor Zeneca ZD2138 (6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2 H-pyran-4-yl])phenoxymethyl]-1-methyl-2-quinolone) was evaluated for its ability to inhibit antigen-induced leukotriene release from guinea-pig lung in vitro and antigen-induced increases in pulmonary resistance in guinea pigs in vivo. ZD2138 inhibited antigen-induced release of leukotriene D 4 and leukotriene B 4 with IC 50 values of 0.3±0.06 μM and 0.4±0.09 μM, respectively. At about ten times higher concentrations, ZD2138 had no effect on antigen-induced release of thromboxane B 2, indicating selectivity for inhibition of 5-lipoxygenase vs. phospholipase A 2, cyclooxygenase, or thromboxane synthetase. Similarly, ZD2138 did not inhibit histamine release, indicating that the compound did not have a generalized effect on the mediator release processes. Zeneca ZM230487 (6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2 H-pyran-4-yl])phenoxymethyl]-1-ethyl-2-quinolone), the N-ethyl analog of ZD2138, was approximately equipotent toward inhibition of antigen-induced leukotriene D 4 release, with an IC 50 of 0.2 ± 0.08 μM. The so-called 5-lipoxygenase activating protein (FLAP) inhibitor, MK-886 (3-[1-( p-chlorobenzyl)-5-(isopropyl)-3- tert-butylthioindol-2-yl]-2, 2-dimethylpropanoic acid), and the iron ligand 5-lipoxygenase inhibitor zileuton ( N-(1-benzo[ b]thien-2-ylethyl)- N-hydroxyurea) were also active, but less potent than ZD2138 with IC 50 values for inhibition of antigen-induced leukotriene release in vitro of 9.3±3.2 μM and 14.8±1.8 μM, respectively. In the guinea-pig in vivo model, ZD2138 and ZM230487, at 1 mg/kg i.v., significantly inhibited aerosol antigen-induced increases in pulmonary resistance. In contrast, MK-886 and zileuton had no significant effect at 1 mg/kg, but at 10 mg/kg significantly inhibited antigen-induced changes in pulmonary resistance. These results demonstrate that ZD2138 and ZM230487 are potent inhibitors of 5-lipoxygenase.