Leukotriene receptor antagonists. 2. The [[(tetrazol-5-ylaryl)oxy]methyl]acetophenone derivatives.
A series of [[(tetrazol-5-ylaryl)oxy]methyl]acetophenones was synthesized and evaluated as antagonists of leukotriene D4 induced contractions of guinea pig ileum. Substitutions at the 3-position of the acetophenone with ethyl (66), propyl (68), butyl (83), and isobutyl (84) gave -log IC50 values of 7.9, 8.0, 7.8, and 7.7, respectively. Equally potent compounds were obtained when the tetrazol-5-yl group was connected to the second benzene ring in the para position with a chemical bond (67), methylene (68), or ethylene (71). For retention of high antagonist activity, the acetophenone should be substituted in the 2-position by a hydroxyl group and the tetrazole ring should have an acidic hydrogen atom. 1-[2-Hydroxy-3-propyl-4-[[4-(1H-tetrazol-5-ylmethy) phenoxy]methyl]phenyl]ethanone (68, LY1632443) has undergone extensive pharmacologic evaluation for its potential as an antiasthma agent.
D000098:Acetophenones / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
D000098:Acetophenones; D001393:Azoles; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D013777:Tetrazoles; C049043:LY 163443