N-[(arylmethoxy)phenyl] and N-[(arylmethoxy)naphthyl] sulfonamides: potent orally active leukotriene D4 antagonists of novel structure.
Two series of compounds, N-[(arylmethoxy)phenyl] sulfonamides and N-[(arylmethoxy)naphthyl] sulfonamides, were prepared as leukotriene D4 (LTD4) antagonists. In the phenyl series, N-[3-(2-quinolinylmethoxy)phenyl]-trifluoromethanesulfonamide (Wy-48,252, 16) was the most potent inhibitor of LTD4-induced bronchoconstriction in the guinea pig. With an intragastric ID50 of 0.1 mg/kg (2-h pretreatment), 16 was 300 times more potent than LY-171,883. Compound 16 also intragastrically inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ID50 of 0.6 mg/kg. In vitro against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and L-cysteine, 16 produced a pKB value of 7.7. In the rat PMN assay 16 inhibited both 5-lipoxygenase and cyclooxygenase (IC50's = 4.6 and 3.3 microM). In the naphthyl series, N-[7-(2-quinolinylmethoxy)-2-naphthyl]trifluoromethanesulfonamide (Wy-48,090, 47) in addition to potent LTD4 antagonist activity (on isolated guinea pig trachea 47 had a pKB value of 7.04) also had antiinflammatory activity (63% inhibition at 50 mg/kg in the rat carrageenan paw edema assay and 34% inhibition of TPA-induced inflammation at 1 mg/ear in the mouse ear edema model). Perhaps the antiinflammatory activity of 47 was due to its additional activity of inhibiting both 5-lipoxygenase and cyclooxygenase enzymes (IC50's = 0.23 and 11.9 microM, respectively, in rat PMN).
Musser
J H
JH
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Kreft
A F
AF
Bender
R H
RH
Kubrak
D M
DM
Carlson
R P
RP
Chang
J
J
Hand
J M
JM
D000098:Acetophenones / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001980:Bronchi; D055598:Chemical Phenomena; D002621:Chemistry; D003251:Constriction, Pathologic / Q000188:drug therapy; D016861:Cyclooxygenase Inhibitors; D003545:Cysteine / Q000494:pharmacology; D004487:Edema / Q000188:drug therapy; D006168:Guinea Pigs; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D016859:Lipoxygenase Inhibitors; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014132:Trachea / Q000187:drug effects
D000098:Acetophenones; D016861:Cyclooxygenase Inhibitors; D006912:Hydroxyquinolines; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D013189:SRS-A; D013449:Sulfonamides; D013777:Tetrazoles; C056398:Wy 48252; C044660:LY 171883; D003545:Cysteine; D007213:Indomethacin