In vivo characterization of hydroxamic acid inhibitors of 5-lipoxygenase

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00394a032

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.