5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (AM679)--a potent FLAP inhibitor.
A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model.
Stock
Nicholas
N
Amira Pharmaceuticals, 9535 Waples St., Suite 100, San Diego, CA 92121, USA. nick.stock@amirapharm.com
Baccei
Christopher
C
Bain
Gretchen
G
Broadhead
Alex
A
Chapman
Charles
C
Darlington
Janice
J
King
Christopher
C
Lee
Catherine
C
Li
Yiwei
Y
Lorrain
Daniel S
DS
Prodanovich
Pat
P
Rong
Haojing
H
Santini
Angelina
A
Zunic
Jasmine
J
Evans
Jilly F
JF
Hutchinson
John H
JH
Prasit
Peppi
P
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015289:Leukotrienes / Q000097:blood / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D010421:Pentanoic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
C549133:3-(5-(-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-(5-methoxypyrimidin-2-yl)-benzyl)-1H-indol-2-yl)-2,2-dimethyl-propionic acid; D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D010421:Pentanoic Acids; C030374:indole