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) D4 receptor antagonist. In the isolated guinea-pig trachea pretreated with
indomethacin (5 microM) and
L-cysteine (10 mM),
Wy-48,252 antagonized TD4-induced contraction with a pKB = 7.6. Against
LTC4 on tissues pretreated with IND and
glutathione (10 mM),
Wy-48,252 had a pKB greater than 5.
Wy-48,252 (10 microM) did not antagonize
pilocarpine-,
histamine- or
PGF2 alpha-induced tracheal contraction. Further, in the presence of
indomethacin and
chlorpheniramine (1 microM),
Wy-48,252 dose-dependently inhibited the
antigen-induced contraction of guinea-pig trachea in a manner consistent with antagonism at the
LTD4 receptor and inhibition of LT synthesis. In the Konzett-Rossler model of i.v. LTD4-induced bronchoconstriction in
indomethacin treated guinea pigs, intragastric
Wy-48,252 (2 hr) had an ID50 of 100 micrograms/kg and a functional half-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 ID50 of 0.6 mg/kg and a 5 hr half life. Intragastric
Wy-48,252 also selectively blocked the cutaneous wheal reaction to intradermal
LTD4 but not
histamine. We conclude that
Wy-48,252 is distinguished from other selective
LTD4 receptor antagonists by its oral potency and should be useful in ascertaining the role of
LTD4 mediated processes in
asthma,
allergy and animal models.