Synthesis and Dual Antagonistic Activity against Thromboxane A₂ and Leukotriene D₄ of [4-[1-(Benzenesulfonamido)alkyl]phenyl]alkanoic Acid Derivatives

抄録

In order to find new antiasthmatic agents with dual antagonistic activity against thromboxane A₂ (TXA₂) and leukotriene D₄ (LTD₄) receptors, synthesis and pharmacological evaluation of various [4-[1-(benzenesulfonamido)-alkyl]phenyl]alkanoic acid derivatives were undertaken. TXA₂ and LTD₄ antagonistic activities in vitro were evaluated by measuring the inhibitory effects on U-46619-induced contraction of guinea-pig trachea and LTD₄-induced contraction of guinea-pig ileum and trachea. Several compounds showed satisfactory dual antagonistic activities, and their effect (after oral administration) on LTD₄-induced bronchoconstriction in guinea-pig in vivo was examined. The results demonstrated that both 4-[4-[1-(4-chlorobenzenesulfonamido)hexyl]phenyl]butyric acid (12e) and 4-[4-[1-(4-chlorobenzenesulfonamido)-5-methylhexyl]phenyl]butyric acid (12m) possessed good anti-LTD₄ activities. Compounds 12e and 12m were then evaluated for other related pharmacological effects involving the arachidonic acid cascade. These compounds appear to be hybrid eicosanoids antagonists having antagonistic activity against contraction of guinea-pig trachea induced by prostaglandin D₂ (PGD₂) and PGF_2α, as well as TXA₂ and LTD₄ antagonistic activities.