The properties of A-69412: a small hydrophilic 5-lipoxygenase inhibitor.
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.
Bell
R L
RL
Immunosciences Research Area, Abbott Laboratories, Abbott Park, IL 60064-3500.
Bouska
J
J
Young
P R
PR
Lanni
C
C
Machinist
J
J
Malo
P E
PE
Summers
J B
JB
Brooks
D W
DW
Carter
G W
GW
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
D001798:Blood Proteins; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C083562:N-1-(fur-3-ylethyl)-N-hydroxyurea; D007975:Leukotriene B4; C063449:zileuton; D006918:Hydroxyurea