Trisubstituted pyridine leukotriene B4 receptor antagonists: synthesis and structure-activity relationships.
A series of trisubstituted pyridines have been prepared that exhibit in vitro leukotriene B4 (LTB4, 1) receptor antagonist activity. Previous disubstituted pyridines from these labs showed high affinity for the LTB4 receptor but demonstrated agonist activity in functional assays (e.g., 2, Ki = 1 nM). Compound 4, the initial lead compound of this new series, showed only modest affinity by comparison (Ki = 282 nM); however, 4 was a receptor antagonist with no demonstrable agonist activity up to 10 microM. Subsequent modifications of the lipid tail and aryl head group region led to the discovery of aniline 50 (SB 201146). This compound, also free of agonist activity, possesses high affinity for the LTB4 receptor (Ki = 4.7 nM).
Daines
R A
RA
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Chambers
P A
PA
Pendrak
I
I
Jakas
D R
DR
Sarau
H M
HM
Foley
J J
JJ
Schmidt
D B
DB
Kingsbury
W D
WD
D000179:Acrylates / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000648:ultrastructure; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
D000179:Acrylates; D011725:Pyridines; D018102:Receptors, Leukotriene B4; D014316:Tritium; C084128:SB 201146; D007975:Leukotriene B4