Inhibition of liver alcohol dehydrogenase and ethanol metabolism by 3-substituted thiolane 1-oxides

3-Substituted thiolane 1-oxides (methyl, n-butyl, n-hexyl, and phenyl) were prepared and tested as inhibitors of horse, monkey, and rat liver alcohol dehydrogenases and of ethanol metabolism in rats. These compounds inhibit alcohol oxidation in an uncompetitive manner with respect to ethanol as a va...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1985-01, Vol.28 (1), p.36-40
Main Authors: Chadha, Vijay K, Leidal, Kevin G, Plapp, Bryce V
Format: Article
Language:English
Subjects:
Alcohol Dehydrogenase
Alcohol Oxidoreductases - antagonists & inhibitors
Animals
Chemistry
Cyclic S-Oxides - chemical synthesis
Cyclic S-Oxides - pharmacology
Ethanol - metabolism
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives
Horses
Kinetics
Lethal Dose 50
Liver - enzymology
Macaca mulatta
Male
Mice
Organic chemistry
Preparations and properties
Rats
Rats, Inbred Strains
Thiophenes - chemical synthesis
Thiophenes - pharmacology
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Summary:3-Substituted thiolane 1-oxides (methyl, n-butyl, n-hexyl, and phenyl) were prepared and tested as inhibitors of horse, monkey, and rat liver alcohol dehydrogenases and of ethanol metabolism in rats. These compounds inhibit alcohol oxidation in an uncompetitive manner with respect to ethanol as a varied substrate. Lengthening the alkyl substituent increased the inhibitory potency because of tighter binding in the hydrophobic substrate binding pocket of the alcohol dehydrogenases. Thus, the 3-hexyl derivative was the most potent inhibitor of the purified rat liver alcohol dehydrogenase, with a Kii value of 0.13 microM. The 3-butyl derivative was the best inhibitor of ethanol metabolism in rats, with a Kii value of 11 mumol/kg. The acute toxicity in mice of the butyl derivative was 1.4 mmol/kg. Since high concentrations of alcohol do not prevent the inhibitory effects of these compounds, they may be particularly useful for preventing poisoning by methanol or ethylene glycol.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00379a009