Synthesis and dual antagonistic activity against thromboxane A2 and leukotriene D4 of [4-[1-(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives.
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 L-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]bu tyric 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 PGF2 sigma, as well as TXA2 and LTD4 antagonistic activities.
Sakurai
S
S
Research and Development Division, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
Ogawa
N
N
Onogi
Y
Y
Takeshita
M
M
Takahashi
H
H
Ohashi
T
T
Kato
K
K
Yasuda
S
S
Kato
H
H
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007074:Immunoglobulin G / Q000276:immunology; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects
D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D007074:Immunoglobulin G; D018077:Receptors, Leukotriene; D013449:Sulfonamides; D013928:Thromboxane A2; D017998:Leukotriene D4