Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methane sulfonamide) an orally active leukotriene D 4 antagonist: Pharmacological characterization in vitro and in vivo in the guinea pig

Abstract

The following communicates the pharmacology of Wy-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide) a chemically novel and orally potent leukotriene (LT) D 4 receptor antagonist. In the isolated guinea-pig trachea pretreated with indomethacin (5 μM) and L-cysteine (10 mM), Wy-48,252 antagonized TD 4-induced contraction with a pK B = 7.6. Against LTC 4 on tissues pretreated with IND and glutathione (10 mM), Wy-48,252 had a pK B > 5. Wy-48,252 (10 μM) did not antagonize pilocarpine-, histamine- or PGF 2α-induced tracheal contraction. Further, in the presence of indomethacin and chlorpheniramine (1 μM), Wy-48,252 dose-dependently inhibited the antigen-induced contraction of guinea-pig trachea in a manner consistent with antagonism at the LTD 4 receptor and inhibition of LT synthesis. In the Konzett-Rossler model of i.v. LTD 4-induced bronchoconstriction in indomethacin treated guinea pigs, intragastric Wy-48,252 (2 hr) had and ID 50 of 100 μg/kg and a functionalhalf-life of 5 hr. Against i.v. antigen-induced bronchoconstriction in guinea pigs treated with indomethacin and chlorpheniramine, intragastric Wy-48,252 (2 hr) had an ID 50 of 0.6 mg/kg and a 5 hr half life. Intragastric Wy-48,252 also selectively blocked the cutaneous wheal reaction to intradermal LTD 4 but not histamine. We conclude that Wy-48,252 is distinguished from other selective LTD 4 receptor antagonists by its oral potency and should be useful in ascertaining the role of LTD 4 mediated processes in asthma, allergy and animal models.