Hydroxyacetophenone-derived antagonists of the peptidoleukotrienes.
Considerations of the possible similarities between leukotriene D4 and its prototypical antagonist, FPL 55712, led to the development of a new series of leukotriene antagonists incorporating a hydroxyacetophenone group (e.g., the toluic acids 16 and 18). Although considerable attention has focused on FPL 55712-derived analogues, only limited investigations into alternatives for the standard 4-acetyl-3-hydroxy-2-propylphenoxy moiety have been reported. Therefore, an extensive study of modifications to the hydroxyacetophenone portion of toluic acid 18 was undertaken. Although no viable alternative to the 3-hydroxy moiety was discovered, replacements for the 2-propyl group (34, 37) and the 4-acetyl functionality (56, 59) yielded potent antagonists. A number of compounds exhibited longer duration of action in vivo than FPL 55712.
Brown
F J
FJ
Department of Medicinal Chemistry, ICI Pharmaceuticals Group, Wilmington, Delaware 19897.
Bernstein
P R
PR
Cronk
L A
LA
Dosset
D L
DL
Hebbel
K C
KC
Maduskuie
T P
TP
Shapiro
H S
HS
Vacek
E P
EP
Yee
Y K
YK
Willard
A K
AK
D000098:Acetophenones; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D001681:Biological Assay; D055598:Chemical Phenomena; D002621:Chemistry; D002867:Chromones / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D006900:Hydroxylation; D007659:Ketones; D008745:Methylation; D009119:Muscle Contraction / Q000187:drug effects; D009584:Nitrogen; D010636:Phenols; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000502:physiology
D000098:Acetophenones; D001565:Benzoates; D002867:Chromones; D007659:Ketones; D010636:Phenols; D013189:SRS-A; C006312:FPL 55712; D009584:Nitrogen