Isosorbide-2-carbamate Esters: Potent and Selective Butyrylcholinesterase Inhibitors

In this study, we report the SAR and characterization of two groups of isosorbide-based cholinesterase inhibitors. The first was based directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. T...

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Veröffentlicht in:Journal of medicinal chemistry 2008-10, Vol.51 (20), p.6400-6409
Hauptverfasser: Carolan, Ciaran G, Dillon, Gerald P, Gaynor, Joanne M, Reidy, Sean, Ryder, Sheila A, Khan, Denise, Marquez, Juan F, Gilmer, John F
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Sprache:eng
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Zusammenfassung:In this study, we report the SAR and characterization of two groups of isosorbide-based cholinesterase inhibitors. The first was based directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. The compounds proved to be potent and selective inhibitors of human plasma butyrylcholinesterase (huBuChE). In the second group, the nitrate ester was removed and replaced with a variety of alkyl and aryl esters. These generally exhibited nanomolar potency with high selectivity for BuChE over acetylcholinesterase (AChE). The most potent and selective compound was isosorbide-2-benzyl carbamate-5-benzoate with an IC50 of 4.3 nM for BuChE and >50000 fold selectivity over human erythrocyte AChE. Inhibition with these compounds is time-dependent, competitive, and slowly reversible, indicating active site carbamylation.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800564y