Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors.
This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-ind ol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models.
Frenette
R
R
Merck Frosst Center for Therapeutic Research, Pointe-Claire - Dorval, Québec, Canada.
Hutchinson
J H
JH
Léger
S
S
Thérien
M
M
Brideau
C
C
Chan
C C
CC
Charleson
S
S
Ethier
D
D
Guay
J
J
Jones
T R
TR
McAuliffe
M
M
Piechuta
H
H
Riendeau
D
D
Tagari
P
P
Girard
Y
Y
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591