Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 4. Addition of chromone moiety enhances leukotriene D4 receptor binding affinity.
The combination of the benzopyran-4-one ring, a moiety found in the prototype leukotriene antagonist, FPL 55,712, with the (2-quinolinylmethoxy)phenyl group led to a significant increase in leukotriene receptor binding affinity. This modification resulted in a 10,000-fold improvement in binding affinity compared to FPL 55,712. Compound 7 (RG 12553), with a Ki value of 0.1 nM, has higher affinity than the natural agonist LTD4 and is one of the most potent LTD4 antagonists reported. The structure-activity relationships of this series of potent leukotriene antagonists are discussed.
Huang
F C
FC
Rhone-Poulenc Rorer Central Research, King of Prussia, Pennsylvania 19406.
Galemmo
R A
RA
Poli
G B
GB
Learn
K S
KS
Morrissette
M M
MM
Johnson
W H
WH
Dankulich
W P
WP
Campbell
H F
HF
Carnathan
G W
GW
VanInwegen
R G
RG
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002867:Chromones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D007191:Indazoles / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002867:Chromones; D007191:Indazoles; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C054217:ICI 198615; C006312:FPL 55712