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])phenoxy- methyl]-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 D4 and leukotriene B4 with IC50 values of 0.3 +/- 0.06 microM and 0.4 +/- 0.09 microM, respectively. At about ten times higher concentrations, ZD2138 had no effect on antigen-induced release of thromboxane B2, indicating selectivity for inhibition of 5-lipoxygenase vs. phospholipase A2, 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 D4 release, with an IC50 of 0.2 +/- 0.08 microM. 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 microM and 14.8 +/- 1.8 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Kusner
E J
EJ
Department of Pharmacology, Zeneca Pharmaceuticals Group, Zeneca, Inc., Wilmington, DE 19897.
Buckner
C K
CK
Dea
D M
DM
DeHaas
C J
CJ
Marks
R L
RL
Krell
R D
RD
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D000941:Antigens / Q000276:immunology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011714:Pyrans / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D002722:Chlorobenzenes
D000941:Antigens; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2; D011714:Pyrans; D015363:Quinolones; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase; C060893:MK-886; D002722:Chlorobenzenes; C075799:ICI D2138; C088450:ZM 230487