THE 5-LIPOXYGENASE INHIBITORS ZD2138 AND ZM230487 ARE POTENT AND SELECTIVE INHIBITORS OF SEVERAL ANTIGEN-INDUCED GUINEA-PIG PULMONARY RESPONSES

The non-redox 5-lipoxygenase inhibitor Zeneca ZD2138 (6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-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 IC50 values of 0.3 +/- 0.06 mu M and 0.4 +/- 0.09 mu M, 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-2H-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 IC50 of 0.2 +/- 0.08 mu M 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-hydroxy urea) were also active, but less potent than ZD2138 with IC50 values for inhibition of antigen-induced leukotriene release in vitro of 9.3 +/- 3.2 mu M and 14.8 +/- 1.8 mu M, 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.