Structure-activity relationships (SAR) of the 3-alkyl substituents among a series of hydroxy-acetophenone leukotriene antagonists.
LY171883 is an orally active antagonist of leukotriene (LT) D4 and LTE4. A series of related compounds varying the position and nature of the alkyl side chain were synthesized and evaluated for their ability to block LTD4-induced contraction of guinea pig ileum. Maximal activity was obtained with n-propyl, n-butyl, and n-pentyl substituents with slightly reduced activity for longer side chains. Polar groups on the side chain substantially reduced activity. Thus, it appears that the leukotriene receptor site requires a nonpolar alkyl group of moderate size at the 3-position on this type of receptor antagonist.
Marshall
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WS
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Whitesitt
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CA
Goodson
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T
Roman
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C
Rinkema
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L
Fleisch
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JH
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology*
D000098:Acetophenones; D001393:Azoles; D013189:SRS-A; D013777:Tetrazoles; C044660:LY 171883