Quantitative structure-activity relationships involving the inhibition of glycolic acid oxidase by derivatives of glycolic and glyoxylic acids

The enzyme glycolic acid oxidase oxidizes glycolate to glyoxylate and glyoxylate to oxalate. Three series of compounds related to the natural substrates, substituted glycolic, oxyacetic, and glyoxylic acids, have been investigated as inhibitors of this enzyme using the techniques of regression analy...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1979-06, Vol.22 (6), p.608-614
Main Authors: Randall, William C, Streeter, Kermit B, Cresson, Emlen L, Schwam, Harvey, Michelson, Stuart R, Anderson, Paul S, Cragoe, Edward J, Williams, Haydn W. R, Eichler, Eva, Rooney, C. Stanley
Format: Article
Language:English
Subjects:
Acetates - pharmacology
Alcohol Oxidoreductases - antagonists & inhibitors
Animals
Glycolates - chemical synthesis
Glycolates - pharmacology
Glyoxylates - chemical synthesis
Glyoxylates - pharmacology
In Vitro Techniques
Keto Acids - pharmacology
Liver - enzymology
Phenoxyacetates - pharmacology
Structure-Activity Relationship
Swine
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Summary:The enzyme glycolic acid oxidase oxidizes glycolate to glyoxylate and glyoxylate to oxalate. Three series of compounds related to the natural substrates, substituted glycolic, oxyacetic, and glyoxylic acids, have been investigated as inhibitors of this enzyme using the techniques of regression analysis and quantitative structure-activity relationships. The best overall correlation with inhibitory potencies was found with the Hansch hydrophobic parameter pi. The classical electronic parameters sigmap, sigmam, F, and R performed poorly. For the substituted glyoxylic acids, a dummy parameter relating to the presence of a nucleophilic group in close proximity to the alpha-carbonyl of the glyoxylate group was found to be highly significant. The syntheses of six novel glycolic and glyoxylic acids are described.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00192a002