Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenase-activating protein (FLAP).
The 5-lipoxygenase-activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability 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), a novel FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose-dependent inhibition of blood LTB(4) production and dose-related inhibition of urinary LTE(4). After a single oral dose (50-1,000 mg) of AM103, the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-dependent manner. After multiple-dose administration (50-1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single- and multiple-dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted.
Bain
G
G
Amira Pharmaceuticals, San Diego, California, USA.
King
C D
CD
Rewolinski
M
M
Schaab
K
K
Santini
A M
AM
Shapiro
D
D
Moran
M
M
van de Wetering de Rooij
S
S
Roffel
A F
AF
Schuilenga-Hut
P
P
Milne
G L
GL
Lorrain
D S
DS
Li
Y
Y
Arruda
J M
JM
Hutchinson
J H
JH
Prasit
P
P
Evans
J F
JF
D058927:5-Lipoxygenase-Activating Proteins; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis*; D017999:Leukotriene E4 / Q000652:urine*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D011422:Propionates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
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; D002352:Carrier Proteins; D007211:Indoles; D008565:Membrane Proteins; D011422:Propionates; D007975:Leukotriene B4; D017999:Leukotriene E4