Substituted (aryloxy)alkanoic acids as antagonists of slow-reacting substance of anaphylaxis.
A series of compounds in which the 4-acetyl-3-hydroxy-2-propylphenoxy moiety of the standard SRS-A antagonist, FPL-55712, is linked by a polymethylene or a polyether chain to substituted (aryloxy)alkanoic acids was prepared. The compounds were evaluated for their ability to antagonize SRS-A-induced contractions of guinea pig ilea and LTE-induced bronchoconstriction in the guinea pig. The results showed that the compounds were all less potent than FPL-55712 in vitro, yet surprisingly, most were more potent by the inhalation route of administration. Some of the most potent analogues were selected for further pharmacological evaluation and, by inhalation, exhibited selective antagonism of leukotrienes as compared with PAF or histamine. In comparison to FPL-55712, compounds 28 and 37 were more potent against LTE (40- and 80-fold, respectively), LTD (4- and 3-fold, respectively), and LTC (27- and 20-fold, respectively) induced bronchoconstriction when tested by inhalation.
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D017999:Leukotriene E4; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D013189:SRS-A / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
D005227:Fatty Acids; D007202:Indicators and Reagents; D010647:Phenyl Ethers; D013189:SRS-A; D017999:Leukotriene E4