Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation.
We evaluated the in vivo pharmacological properties of AM803 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, a selective five-lipoxygenase-activating protein (FLAP) inhibitor, using rat and mouse models of acute inflammation. Oral administration of AM803 (1 mg/kg) resulted in sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with >90% inhibition for up to 12 h and an EC50 of approximately 7 nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50s of 0.12 mg/kg and 0.37 mg/kg, respectively. The inhibition measured 16 h following a single oral dose of 3 mg/kg was 86% and 41% for LTB4 and CysLTs, respectively. In an acute inflammation setting, AM803 dose-dependently reduced LTB4, CysLTs, plasma protein extravasation and neutrophil influx induced by peritoneal zymosan injection. Finally, AM803 increased survival time in mice exposed to a lethal intravenous injection of platelet activating factor (PAF). The magnitude of effect was similar to that of an inhibitor of five-lipoxygenase (5-LO) and LTA4 hydrolase but superior to a leukotriene CysLT1 receptor antagonist. In summary, AM803 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute inflammation and in a model of lethal shock.
Lorrain
Daniel S
DS
Amira Pharmaceuticals, 9535 Waples Street, Ste. 100, San Diego, California 92121, USA. dan.lorrain@amirapharm.com
Bain
Gretchen
G
Correa
Lucia D
LD
Chapman
Charles
C
Broadhead
Alex R
AR
Santini
Angelina M
AM
Prodanovich
Patricia P
PP
Darlington
Janice V
JV
Stock
Nicholas S
NS
Zunic
Jasmine
J
King
Christopher D
CD
Lee
Catherine
C
Baccei
Christopher S
CS
Stearns
Brian
B
Roppe
Jeffrey
J
Hutchinson
John H
JH
Prasit
Peppi
P
Evans
Jilly F
JF
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002908:Chronic Disease; D003545:Cysteine / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D010421:Pentanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000494:pharmacology; D011422:Propionates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013379:Substrate Specificity; D015054:Zymosan / Q000494:pharmacology
C552410:3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; C548594:Alox5ap protein, rat; D002352:Carrier Proteins; D007211:Indoles; D015289:Leukotrienes; D008565:Membrane Proteins; D010421:Pentanoic Acids; D010972:Platelet Activating Factor; D011422:Propionates; C112381:cysteinyl-leukotriene; D007975:Leukotriene B4; D015054:Zymosan; C029658:propionic acid; D003545:Cysteine