Inhibition of human alcohol dehydrogenases by formamides.

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Schindler JF, Berst KB, Plapp BV

Inhibition of human alcohol dehydrogenases by formamides.

J Med Chem. 1998 May 7;41(10):1696-701.

PubMed ID
9572895 [ View in PubMed
]
Abstract

Human alcohol dehydrogenase (HsADH) comprises class I (alpha, beta, and gamma), class II (pi), and class IV (sigma) enzymes. Selective inhibitors of the enzymes could be used to prevent the metabolism of alcohols that form toxic products. Formamides are unreactive analogues of aldehydes and bind to the enzyme-NADH complex [Ramaswamy, S.; Scholze, M.; Plapp, B. V. Biochemistry 1997, 36, 3522-3527]. They are uncompetitive inhibitors against varied concentrations of alcohol, and this makes them effective even with saturating concentrations of alcohols. Molecular modeling led to the design and synthesis of a series of cyclic, linear, and disubstituted formamides. Evaluation of 23 compounds provided structure-function information and selective inhibitors for the enzymes, which have overlapping but differing substrate specificities. Monosubstituted formamides are good inhibitors of class I and II enzymes, and disubstituted formamides are selective for the alpha enzyme. Selective inhibitors, with Ki values at pH 7 and 25 degrees C of 0.33-0.74 microM, include N-cyclopentyl-N-cyclobutylformamide for HsADH alpha, N-benzylformamide for HsADH beta1, N-1-methylheptylformamide for HsADH gamma2, and N-heptylformamide for HsADH sigma and HsADH beta1.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CyclohexylformamideAlcohol dehydrogenase 1CKi (nM)5200N/AN/ADetails
N-1-methylheptylformamideAlcohol dehydrogenase 1CKi (nM)410N/AN/ADetails
N-BenzylformamideAlcohol dehydrogenase 1BKi (nM)330N/AN/ADetails
N-Cyclopentyl-N-CyclobutylformamideAlcohol dehydrogenase 1AKi (nM)360N/AN/ADetails
N-HeptylformamideAlcohol dehydrogenase 1BKi (nM)330N/AN/ADetails