title: The properties of A-69412: a small hydrophilic 5-lipoxygenase inhibitor.
abstract: A compound which inhibits leukotriene biosynthesis could be clinically useful in treating several allergic and inflammatory diseases. One site for such inhibition is at the enzyme 5-lipoxygenase. Most inhibitors of this enzyme thus far described are poorly bioavailable. A-69412 is a small, relatively hydrophilic compound of the N-hydroxyurea class, which exhibits minimal plasma protein binding (6-12%). The compound was found to be a potent long-acting inhibitor of leukotriene formation in vivo in the rat (oral ED50 = 5 mg/kg) and ex vivo in several species. In addition, the compound exhibits excellent bioavailability in dogs and monkeys with a relatively long elimination half-life in both the species (6 and 3 h, respectively). The biochemical activity and pharmacological profile of A-69412 indicates its potential utility in asthma and ulcerative colitis, and possibly other inflammatory and allergic conditions.
authors.affiliation: Immunosciences Research Area, Abbott Laboratories, Abbott Park, IL 60064-3500.
authors.forename: R L
authors.initials: RL
authors.lastname: Bell
authors.forename: J
authors.initials: J
authors.lastname: Bouska
authors.forename: P R
authors.initials: PR
authors.lastname: Young
authors.forename: C
authors.initials: C
authors.lastname: Lanni
authors.forename: J
authors.initials: J
authors.lastname: Machinist
authors.forename: P E
authors.initials: PE
authors.lastname: Malo
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
authors.forename: D W
authors.initials: DW
authors.lastname: Brooks
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000707:Anaphylaxis / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D006207:Half-Life; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
chemical_list: D001798:Blood Proteins; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C083562:N-1-(fur-3-ylethyl)-N-hydroxyurea; D007975:Leukotriene B4; C063449:zileuton; D006918:Hydroxyurea