Hydroxamic acid inhibitors of 5-lipoxygenase

The hydroxamic acid functionality can be incorporated in a variety of simple molecules to produce potent inhibitors of 5-lipoxygenase. As an example of this, the structure-activity relationships in a series of omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids are presented. Among the featur...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1987-03, Vol.30 (3), p.574-580
Main Authors: Summers, James B, Mazdiyasni, Hormoz, Holms, James H, Ratajczyk, James D, Dyer, Richard D, Carter, George W
Format: Article
Language:English
Subjects:
Arachidonate Lipoxygenases - antagonists & inhibitors
Biological and medical sciences
Cell Line
General pharmacology
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - pharmacology
Kinetics
Lipoxygenase Inhibitors
Magnetic Resonance Spectroscopy
Medical sciences
Molecular Conformation
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Protein Binding
Structure-Activity Relationship
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The hydroxamic acid functionality can be incorporated in a variety of simple molecules to produce potent inhibitors of 5-lipoxygenase. As an example of this, the structure-activity relationships in a series of omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids are presented. Among the features described are the influence of hydrophobicity, aryl substitution, and modifications of the hydroxamate group on enzyme inhibitory potency. To assist in the selection of more potent hydroxamic acid inhibitors, a simple hypothesis about the nature of enzyme-inhibitor binding was devised. In this hypothesis, the structures of compounds were matched to a proposed geometry of arachidonic acid when bound to the enzyme. Compounds that match best without extending into disfavored regions were predicted to be the best inhibitors. Three series of hydroxamates selected according to this approach are described. Within these series are some of the most potent inhibitors of 5-lipoxygenase reported to date.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00386a022