Leukotriene receptor antagonists. 4. Synthesis and leukotriene D4/E4 receptor antagonist activity of 4-(alkyl)acetophenone derivatives.
Analogues of the leukotriene D4/E4 receptor antagonist LY171883 (1a) were synthesized in which the tetrazole was linked to the hydroxyacetophenone moiety by an all-methylene carbon chain. A key step in the synthesis involved a Wittig olefin-forming reaction between 3-methoxy-2-propylbenzaldehyde and the ylide derived from (4-carboxybutyl)triphenylphosphonium bromide to form the desired carbon chain. A regioselective Fries rearrangement was employed to form the o-hydroxyacetophenone. Compounds in which the tetrazole was separated from the acetophenone by four and five methylene groups were compared to the corresponding derivatives in which an oxygen atom linked the tetrazole chain to the aromatic ring for their ability to antagonize LTD4- or LTE4-induced contractions of the isolated guinea pig ileum. When compared to 1a, the "carba" analogue, 7a, showed nearly identical LTD4 antagonist activity. The LTE4 antagonist activity for these two compounds was also identical. In the shorter chain series, the "carba" analogue, 7b, showed enhanced LTD4 antagonist activity and approximately 10-fold greater LTE4 antagonist activity. These results suggest that the oxygen atom para to the acetyl group of 1a and 1b is not of major importance for association with the LTD4 or LTE4 receptor sites in the guinea pig ileum.
Gapinski
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Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Roman
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Rinkema
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Fleisch
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D000098:Acetophenones / Q000138:chemical synthesis* / Q000494:pharmacology; D000478:Alkylation; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007537:Isometric Contraction / Q000187:drug effects; D017999:Leukotriene E4; D008297:Male; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism*; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000098:Acetophenones; D007202:Indicators and Reagents; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D017999:Leukotriene E4