title: Pharmacological characterization 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 selective 5-lipoxygenase-activating protein inhibitor that reduces acute and chronic inflammation.
abstract: Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 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) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.
authors.affiliation: Amira Pharmaceuticals, San Diego, California 92121, USA. dan.lorrain@amirapharm.com
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lorrain
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Correa
authors.forename: Charles
authors.initials: C
authors.lastname: Chapman
authors.forename: Alex R
authors.initials: AR
authors.lastname: Broadhead
authors.forename: Angelina M
authors.initials: AM
authors.lastname: Santini
authors.forename: Pat
authors.initials: P
authors.lastname: Prodanovich
authors.forename: Janice V
authors.initials: JV
authors.lastname: Darlington
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.forename: Catherine
authors.initials: C
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Baccei
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Jeannie M
authors.initials: JM
authors.lastname: Arruda
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015054:Zymosan
chemical_list: 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; C548594:Alox5ap protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D007211:Indoles; D008565:Membrane Proteins; D011422:Propionates; D007975:Leukotriene B4; D015054:Zymosan