Optimization of the potency and duration of action of N-hydroxyurea 5-lipoxygenase inhibitors.
As in vitro glucuronidation assay and several biochemical assays were utilized to discover potent new N-hydroxyurea-containing 5-lipoxygenase inhibitors with long durations of action. The best of these, A-78773, is a racemic mixture of two enantiomers. These enantiomers were purified and the R(+)-enantiomer A-79175 was found to be superior to the S(-)-enantiomer with respect to in vitro metabolism and duration of action in the monkey. A-79175 was a potent selective inhibitor of 5-hydroxyeicosatetraenoic acid formation in rat basophilic leukemic homogenates (IC50 = 54 nM) and of calcium ionophore-induced leukotriene B4 (LTB4) formation in purified human polymorphonuclear leukocytes (IC50 = 25 nM) and human whole blood (IC50 = 80 nM). The compound inhibited LT formation in the rat with oral ED50s of 1 to 2 mg/kg. It also was a potent inhibitor of edema and inflammatory cell influx in rats and mice. A-79175 was resistant to glucuronidation and had an elimination half-life of nearly 9 hr in cynomolgus monkeys. A-79175 inhibited ex vivo LTB4 formation by monkeys for extended periods. A single 0.5-mg/kg oral dose gave > 50% inhibition of calcium ionophore-induced LTB4 formation ex vivo for 12 hr. A good correlation was found between the elimination half-life for A-78773 and its enantiomers in cynomolgus monkeys and humans. These data indicate that A-79175 is a promising long-acting agent that should be useful to delineate the importance of LTs in animal and human studies.
Bell
R L
RL
Immunosciences Research Area, Abbott Laboratories, Abbott Park, Illinois.
Bouska
J B
JB
Malo
P E
PE
Lanni
C
C
Harris
R R
RR
Otis
E R
ER
Stewart
A O
AO
Brooks
D W
DW
Carter
G W
GW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D051379:Mice; D051381:Rats; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; C082739:A 78773; D007975:Leukotriene B4; C063449:zileuton; D006918:Hydroxyurea