In vivo characterization of hydroxamic acid inhibitors of 5-lipoxygenase

The hydroxamic acid functionally can be incorporated into simple molecules to produce potent inhibitors of 5-lipoxygenase. The ability of many of these hydroxamates to inhibit leukotriene synthesis in vivo has been measured directly with a rat peritoneal anaphylaxis model. Despite their potent enzym...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-11, Vol.30 (11), p.2121-2126
Main Authors: Summers, James B, Gunn, Bruce P, Mazdiyasni, Hormoz, Goetze, Andrew M, Young, Patrick R, Bouska, Jennifer B, Dyer, Richard D, Brooks, Dee W, Carter, George W
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Arachidonate Lipoxygenases - antagonists & inhibitors
Biological and medical sciences
General pharmacology
Hydroxamic Acids - metabolism
Hydroxamic Acids - pharmacokinetics
Hydroxamic Acids - pharmacology
Lipoxygenase Inhibitors
Male
Medical sciences
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Rats
Rats, Inbred Strains
SRS-A - biosynthesis
Structure-Activity Relationship
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Summary:The hydroxamic acid functionally can be incorporated into simple molecules to produce potent inhibitors of 5-lipoxygenase. The ability of many of these hydroxamates to inhibit leukotriene synthesis in vivo has been measured directly with a rat peritoneal anaphylaxis model. Despite their potent enzyme inhibitory activity in vitro, many orally dosed hydroxamic acids only weakly inhibited leukotriene synthesis in vivo. This discrepancy is attributable at least in part to the rapid metabolism of hydroxamates to the corresponding carboxylic acids, which are inactive against the enzyme. A study of the structural features that affect this metabolism revealed that 2-arylpropionohydroxamic acids are relatively resistant to metabolic hydrolysis. Several members of this class of hydroxamates are described that are orally active inhibitors of leukotriene synthesis.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00394a032