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A-78773: a selective, potent 5-lipoxygenase inhibitor
R L Bell1, D W Brooks, P R Young
1Immunosciences Research Area, Abbott Park, IL 60064.
Journal of Lipid Mediators
|March 1, 1993
Summary
A new drug, A-78773, is a potent inhibitor of 5-lipoxygenase, effectively blocking leukotriene formation. This compound shows promise for treating inflammatory diseases mediated by leukotrienes.
Area of Science:
- Biochemistry
- Pharmacology
Background:
- Leukotrienes are key mediators in inflammatory diseases.
- 5-lipoxygenase is a critical enzyme in leukotriene synthesis.
Purpose of the Study:
- To evaluate the potency and selectivity of A-78773, a novel 5-lipoxygenase inhibitor.
- To compare A-78773 with existing inhibitors like zileuton.
Main Methods:
- In vitro assays measuring leukotriene formation in cell-free lysates and isolated human neutrophils.
- Enzyme inhibition assays using RBL cell lysate, rabbit reticulocyte, and human platelet lipoxygenases.
- Ex vivo and in vivo studies in dogs and rats to assess oral activity and duration of action.
Main Results:
- A-78773 demonstrated significantly higher potency than zileuton in inhibiting leukotriene formation.
- A-78773 selectively inhibited RBL cell lysate 5-lipoxygenase at much lower concentrations than other lipoxygenase isoforms.
- The compound exhibited potent, long-lasting, orally active inhibition of leukotriene formation in vivo and ex vivo.
- Complete inhibition of leukotriene formation by A-78773 did not affect other eicosanoid pathways.
Conclusions:
- A-78773 is a highly potent and selective 5-lipoxygenase inhibitor.
- A-78773's oral activity and long duration suggest clinical utility.
- A-78773 represents a promising therapeutic agent for leukotriene-mediated diseases.