ABT-761 attenuates bronchoconstriction and pulmonary inflammation in rodents.
Our primary goal has been to discover leukotriene biosynthesis inhibitors with characteristics that are appropriate for use as clinical agents. The success of the use of zileuton in the treatment of asthma led us to explore further the use of the N-hydroxyurea class of 5-lipoxygenase inhibitors as longer-acting compounds with good lung penetration. A variety of in vitro and in vivo methods were used to evaluate a large number of compounds, from which ABT-761 [(R)-N-(3-(5-(4-fluorophenylmethyl)thien-2-yl)-1-methyl-2-pr opynyl)-N-hydroxyurea] was selected for study. ABT-761 exhibited potent and selective inhibition of leukotriene formation both in vitro and in vivo. More importantly, the compound potently inhibited antigen-induced bronchospasm in guinea pigs when given either prophylactically or therapeutically. In addition, ABT-761 was a potent inhibitor of eosinophil influx into the lungs of Brown Norway rats. These data provide added support for the role of leukotrienes in both bronchospasm and eosinophilic inflammation and characterize ABT-761 as a particularly potent inhibitor of leukotrienes formed in pulmonary tissues. These data combined with the excellent pharmacokinetic characteristics of the compound indicate its potential use in the treatment of leukotriene-dependent human disease.
Bell
R L
RL
Immunosciences Research Area, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Harris
R R
RR
Malo
P E
PE
Bouska
J B
JB
Shaughnessy
T K
TK
Hulkower
K I
KI
Brooks
C D
CD
Carter
G W
GW
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004804:Eosinophils / Q000473:pathology; D006168:Guinea Pigs; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D017999:Leukotriene E4 / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology; D051381:Rats
D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D017999:Leukotriene E4; C096921:atreleuton; D006918:Hydroxyurea