5-lipoxygenase-activating protein inhibitors: development of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103).
The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC(50) of 349 nM in the human blood LTB(4) inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers.
Hutchinson
John H
JH
Departments of Chemistry, Amira Pharmaceuticals, San Diego, California 92121, USA. john.hutchinson@amirapharm.com
Li
Yiwei
Y
Arruda
Jeannie M
JM
Baccei
Christopher
C
Bain
Gretchen
G
Chapman
Charles
C
Correa
Lucia
L
Darlington
Janice
J
King
Christopher D
CD
Lee
Catherine
C
Lorrain
Dan
D
Prodanovich
Pat
P
Rong
Haojing
H
Santini
Angelina
A
Stock
Nicholas
N
Prasit
Peppi
P
Evans
Jilly F
JF
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D011422:Propionates / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
C544814:3-(3-tert-butylsulfanyl-1-(4-(6-methoxypyridin-3-yl)benzyl)-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D006571:Heterocyclic Compounds; D007211:Indoles; D008565:Membrane Proteins; D011422:Propionates; D007975:Leukotriene B4