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 H-pyran-4-yl])phe noxymethyl]-1-methyl-2-quinolone) was evaluated for its ability to inh ibit 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 a nd 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, ZD21 38 had no effect on antigen-induced release of thromboxane B-2, indica ting selectivity for inhibition of 5-lipoxygenase vs. phospholipase A( 2), cyclooxygenase, or thromboxane synthetase. Similarly, ZD2138 did n ot inhibit histamine release, indicating that the compound did not hav e a generalized effect on the mediator release processes. Zeneca ZM230 487 H-pyran-4-yl])phenoxymethyl]-1-ethyl-2-quinolone), the N-ethyl ana log of ZD2138, was approximately equipotent toward inhibition of antig en-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-8 86 -3-tert-butylthioindol-2-yl]-2,2-dimethylpropanoic acid), and the i ron ligand 5-lipoxygenase inhibitor zileuton (N-(1-benzo[b]thien-2-yle thyl)-N-hydroxy urea) were also active, but less potent than ZD2138 wi th IC50 values for inhibition of antigen-induced leukotriene release i n vitro of 9.3 +/- 3.2 mu M and 14.8 +/- 1.8 mu M, respectively. In th e guinea-pig in vivo model, ZD2138 and ZM230487, at 1 mg/kg i.v., sign ificantly inhibited aerosol antigen-induced increases in pulmonary res istance. In contrast, MK-886 and zileuton had no significant effect at 1 mg/kg, but at 10 mg/kg significantly inhibited antigen-induced chan ges in pulmonary resistance. These results demonstrate that ZD2138 and ZM230487 are potent inhibitors of 5-lipoxygenase.