Conformationally restricted leukotriene receptor antagonists: [(octahydro-2-oxo-7-tetradecylidene-2H-1-benzopyran-8-yl)thio]ace tic acids.
[(Octahydro-2-oxo-7-tetradecylidene-2H-1-benzopyran-8-yl)thio]acet ic acid (MDL 43,291) is a novel leukotriene (LT) receptor antagonist. It is a competitive antagonist of LTD4 (pA2 = 6.7) and LTE4 (pA2 = 6.7) and an apparent noncompetitive inhibitor of LTC4 ('pseudo' pA2 = 6.8) in the longitudinal muscle of the guinea pig ileum. At concentrations that effectively antagonize peptidoleukotriene-induced contractions, MDL 43,291 does not antagonize histamine, carbachol or substance P. In vivo, 10-30 mg/kg MDL 43,291, given intravenously, effectively inhibits increases in insufflation pressure induced by 100 ng/kg i.v. LTD4. This compound is a prototype of a novel class of leukotriene receptor antagonists that may be useful in the treatment of bronchial asthma and related disorders.
Gieske
T H
TH
Merrell Dow Research Institute, Cincinnati, Ohio.
Sabol
J S
JS
Weintraub
P M
PM
Raddatz
R
R
Cregge
R J
RJ
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D007783:Lactones / Q000494:pharmacology*; D017999:Leukotriene E4; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology*
D002867:Chromones; D007783:Lactones; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013440:Sulfides; C066886:MDL 43291; D017999:Leukotriene E4; C006312:FPL 55712