Effect of BI-L-239, A-64077 and MK-886 on leukotriene B4 synthesis by chopped guinea pig lung and on antigen-induced tracheal contraction in vitro.
The 5-lipoxygenase (5-LO) inhibitors BI-L-239 and A-64077 were compared with the 5-LO translocation inhibitor MK-886 for the ability to inhibit leukotriene B4 (LTB4) biosynthesis by chopped (1 mm3) guinea pig lung. LTB4 synthesis by ovalbumin-sensitized chopped lung tissue was determined after stimulation with either calcium ionophore (A23187) or antigen. With A23187 stimulation, MK-886 was more potent (IC50 = 0.39 +/- 0.23 microM, mean +/- SEM, p < 0.01) than BI-L-239 (IC50 = 2.48 +/- 0.46 microM) or A-64077 (IC50 = 4.68 +/- 0.70 microM) and BI-L-239 was more potent than A64077 (p < 0.02). Thus, the order of potency was MK-886 > BI-L-239 > A-64077 for inhibition of calcium ionophore-induced LTB4 generation. There was no significant differences in potency of the compounds in chopped lung stimulated with antigen: IC50 for LTB4 synthesis by A-64077 = 3.31 +/- 1.70 microM, for BI-L-239 = 9.06 +/- 4.94 microM, and for MK-886 = 13.33 +/- 7.91 microM. The ability of these compounds to inhibit contraction of tracheal tissue from actively sensitized guinea pigs in response to antigen was also determined in the presence of indomethacin (15 micrograms/ml), mepyramine, and atropine (5 micrograms each/ml). Both 5-LO inhibitors inhibited antigen-induced contraction, with IC50 values for BI-L-239 and A-64077 of 1.58 and 4.35 microM respectively. MK-886 was ineffective at inhibiting antigen-induced tracheal contraction in vitro at concentrations up to 30 microM. In summary, these compounds inhibit antigen-induced and A23187-induced leukotriene biosynthesis in guinea pig tissue. These 5-LO inhibitors were similarly effective at inhibiting antigen-induced tracheal contraction where MK-886 was ineffective.
Noonan
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Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877.
Jamieson-Leclercq
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Desai
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D000818:Animals; D006168:Guinea Pigs; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010636:Phenols / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D002722:Chlorobenzenes
D006918:Hydroxyurea; D007211:Indoles; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D010047:Ovalbumin; D010636:Phenols; C060893:MK-886; D002722:Chlorobenzenes; C067524:enofelast; C063449:zileuton