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N-[(arylmethoxy)phenyl] and N-[(arylmethoxy)naphthyl] sulfonamides: potent orally active leukotriene D4 antagonists of novel structure.
Musser, J H; Kreft, A F; Bender, R H; Kubrak, D M; Carlson, R P; Chang, J; Hand, J M.
Afiliação
  • Musser JH; Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
J Med Chem ; 32(6): 1176-83, 1989 Jun.
Article em En | MEDLINE | ID: mdl-2498516
ABSTRACT
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).
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sulfonamidas / SRS-A Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 1989 Tipo de documento: Article
Buscar no Google
Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sulfonamidas / SRS-A Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 1989 Tipo de documento: Article