Identification and Characterization of Novel Benzil (Diphenylethane-1,2-dione) Analogues as Inhibitors of Mammalian Carboxylesterases
| Autor: | Carol C. Edwards, Philip M. Potter, Paul P. Beroza, Christopher L. Morton, Xin Wei, Kyoung Jin P. Yoon, Randy M. Wadkins, Komath Damodaran, Janice L. Hyatt, and Mary K. Danks, John C. Obenauer, Monika Wierdl |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Databases Factual Molecular model Stereochemistry Quantitative Structure-Activity Relationship Phenylglyoxal Chemical synthesis Carboxylesterase Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Humans Moiety Umbelliferones Butyrylcholinesterase chemistry.chemical_classification biology Rats Intestines Enzyme chemistry Biochemistry Enzyme inhibitor Acetylcholinesterase biology.protein Molecular Medicine Cholinesterase Inhibitors Benzil Carboxylic Ester Hydrolases |
| Zdroj: | Journal of Medicinal Chemistry. 48:2906-2915 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm049011j |
| Popis: | Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K(i) values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K(i) (r(2)0.91), with cross-validation coefficients (q(2)) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed. |
| Databáze: | OpenAIRE |
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