INHIBITION OF ANTIGEN-INDUCED CONTRACTION OF GUINEA-PIG AIRWAYS BY A LEUKOTRIENE SYNTHESIS INHIBITOR, BAY X1005

BAY x1005 ((R)-2-[4-quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid), an inhibitor of leukotriene synthesis, was evaluated, both in vitro and in vivo, for inhibition of antigen-induced airway contraction in the sensitised guinea-pig. Antigen (ovalbumin 0.001-10 mu g/ml) challenge of tracheae in the presence of pyrilamine and indomethacin induced contractile responses which were inhibited by BAY x1005 with an IC50 value of 0.36 (0.2-0.8) mu M. Using the same test system BAY x1005 (1 mu M), ICI D2138 (0.3 mu M) Or AA 861 (1 mu M) had similar inhibitory activities, whereas MK 886, MK 591, and Zileuton (A64077) all tested at 1 mu M and REV 5901 (10 mu M) had no significant effect. Using tracheae from non-sensitised (control) guinea-pigs the calcium ionophore A23187 (1 mu M) induced a maximal contraction which was significantly inhibited by BAY x1005 at 1 mu M, whereas MK 886 was only active at 3 mu M. BAY x1005 tested at 10 mu M and 3 mu M had no effect against leukotriene D-4- or KCl-induced contractions of guinea-pig tracheae respectively. In the anaesthetised ovalbumin sensitised guinea-pig BAY x1005 caused a dose-related inhibition of ovalbumin-induced bronchoconstriction, with approximate ID50 values of 0.85 mg/kg i.v. and 6.3 mg/kg p.o. In the same model MK 886, MK 591, AA 861 and ICI D2138 each given at 10 mg/kg p.o. had no significant inhibitory activity against antigen challenge. Six hours after administration BAY x1005 (10 mg/kg p.o.) was still effective against the antigen-induced response. BAY x1005 (10 mg/kg i.v.) was inactive against leukotriene D-4-, histamine-, platelet activating factor- or U46619-induced bronchoconstriction. BAY x1005 is a potent and longlasting inhibitor of antigen-induced airway responses in the guinea-pig and as such warrants evaluation as an anti-asthmatic agent in man.