Alcohol dehydrogenase inhibitors

Mechanism of Action An alcohol dehydrogenase inhibitor that inhibits the enzyme that catalyzes the metabolism of ethanol, ethylene glycol, and methanol to their toxic metabolites. Therapeutic Effect Inhibits conversion of ethylene glycol and methanol into toxic metabolites. 

Baslow M. H., Suckow R. F., and Hungund B. L. (2000). Effects of ethanol and of alcohol dehydrogenase inhibitors on the reduction of N-acetylaspartate levels of brain in mice in vivo a search for substances that may have therapeutic value in the treatment of Canavan disease. J. Inherit. Metab Dis. 23 684-692. 

Fomepizole (4-methylpyrazole) is an alcohol dehydrogenase inhibitor. It is administered in cases of suspected or confirmed ingestion and intoxication with ethylene glycol or methanol. Fomepizole should be administered intravenously as a loading dose of 15 mg kg followed by doses of 10mgkg every 12 h for four doses, then 15 mg kg every 12 h... 

Some of the most important aromatic pyrazoles with biological activity are shown in Table 38. Pyrazole itself and several A-unsubstituted pyrazoles are inhibitors and deactivators of liver alcohol dehydrogenase (79JMC356, 79ACS(B)483, B-79MI40414, 82ACS(B)10l). 

The crystal structure of the HNL isolated from S. bicolor (SbHNL) was determined in a complex with the inhibitor benzoic acid." The folding pattern of SbHNL is similar to that of wheat serine carboxypeptidase (CP-WII)" and alcohol dehydrogenase." A unique two-amino acid deletion in SbHNL, however, is forcing the putative active site residues away from the hydrolase binding site toward a small hydrophobic cleft, thereby defining a completely different active site architecture where the triad of a carboxypeptidase is missing. 

Figure 17.8 Catal3ftic zinc center of horse liver alcohol dehydrogenase revealed from an X-ray crystallographic structure (PDB file 20HX) [Al-Karadaghi et al., 1994]. The bound NADH cofactor, a molecule of the inhibitor dimethylsulfoxide (DMSO), and the amino acid residues that coordinate the Zn are shown as sticks shaded according to the elements, and the Zn center is shown as a gray sphere, while the protein is shown in thin gray lines.

Similarly, whole-cell Lactobacillus kefir DSM 20587, which possesses two alcohol dehydrogenases for both asymmetric reduction steps, was applied in the reduction of tert-butyl 6-chloro-3,5-dioxohexanoate for asymmetric synthesis of ft rf-butyl-(31 ,5S)-6-chloro-dihydroxyhexanoate (Figure 7.5), a chiral building block for the HMG-CoA reductase inhibitor [ 17]. A final product concentration of 120 him and a specific product capacity of 2.4 mmol per gram dry cell were achieved in an optimized fed-batch process. Ado 99% was obtained for (3R,5S)- and (3.S, 55)-te/ f-butyl-6-chloro-dihydroxyhexanoate with the space-time yield being 4.7 mmolL-1 h-1. 

Disulfiram (Antabuse). Disnlfiram is the only medication specifically approved by the FDA as an aversion therapy for snbstance abnse, specifically alcohol abnse or dependence. Disnlfiram s mechanism of action is qnite simple it is an inhibitor of alcohol dehydrogenase, the major enzyme responsible for the metabolism. Inhibiting this enzyme resnlts in the accnmnlation of acetylaldehyde. Acetylaldehyde is primarily responsible for many of the nnmistakable symptoms of a hangover, and when it accnmnlates in the presence of disnlfiram, it produces a constellation of very nncomfortable physical symptoms. 

The enzyme chemistry of cyclopropylmethanols has been studied both as inhibitors and mechanistic probes [4, 47]. Thus, a series of alkylcyclopropyl-methanol derivatives have been proved as being inhibitors of horse liver alcohol dehydrogenase. There are two sites in the cyclopropylmethanol inhibitors able of reacting with nucleophiles ... 

Alberty analyzed the anion effect on pH-rate data. He first considered a one-substrate, one-product enzyme-catalyzed reaction in which all binding interactions were rapid equilibrium phenomena. He obtained rate expressions for effects on F ax and thereby demonstrating how an anion might alter a pH-rate profile. He also considered how anions may act as competitive inhibitors. The effect of anions on alcohol dehydrogenase has also been investigated. Chloride ions appear to affect the on- and off-rate constants for NAD and NADH binding. See also pH Studies Activation Optimum pH... 

A potent five-membered heterocyclic inhibitor (the chemical systematic name is 1,2-diazole) that strongly inhibits liver alcohol dehydrogenase. See Alcohol Dehydrogenase... 

Drug Treatment of Chronic Alcoholism (Aldehyde Dehydrogenase Inhibitors)... 

As with methanol poisoning, early fomepizole or ethanol infusion and hemodialysis are standard treatments for ethylene glycol poisoning. Fomepizole, an inhibitor of alcohol dehydrogenase, has FDA approval for treatment of ethylene glycol poisoning in adults based on its ability to decrease concentrations of toxic metabolites in blood and urine and to prevent... 

Hansch, C. et al. (1986) A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase. J. Med. Chem., 29 (5), 615-620. 

Uncompetitive inilibitors of liver alcohol dehydrogenase (Chapter 15) could be used to treat cases of poisoning by methanol or ethylene glycol.81 83 The aim is to prevent rapid oxidation to the toxic acids HCOOH and HOCH2COOH, which lower blood pH, while the alcohols are excreted. Uncompetitive inhibitors have an advantage over competitive inhibitors as therapeutic agents in that the inhibition is not overcome when the substrate concentration is saturating.84... 

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