Leukotriene receptor antagonists. III. Pharmacological and chemical studies with LY137617, a leukotriene D4 and leukotriene E4 receptor antagonist.
A series of chlorophenoxyalkyl acids were prepared and evaluated as pharmacological antagonists of leukotriene D4. Structure-activity relationship studies pointed to LY137617 as a compound with possible therapeutic value. In experiments on isolated smooth muscles from the guinea-pig, this agent was a selective and moderately potent antagonist of leukotriene D4 and also leukotriene E4. Other in vitro experiments demonstrated that LY137617 had a high affinity for protein molecules. This was reflected in vivo as a weaker than expected efficacy against leukotriene-mediated events, limiting the compound's potential as a clinical candidate. Nevertheless, agents of this type will prove useful in the laboratory to increase knowledge of leukotriene receptor-antagonist interactions.
Herron
D K
DK
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Whitesitt
C A
CA
Mallet
B E
BE
Rinkema
L E
LE
Haisch
K D
KD
Fleisch
J H
JH
D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000378:metabolism; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000032:analysis / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
D001393:Azoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D013189:SRS-A; D013777:Tetrazoles; D007975:Leukotriene B4; D017999:Leukotriene E4; C058564:5-(4-(3,4-dichloro-2-propylphenoxy)butyl)-1H-tetrazole