%0 Journal Article %1 doi:10.1021/jm800564y %A Carolan, Ciaran G. %A Dillon, Gerald P. %A Gaynor, Joanne M. %A Reidy, Sean %A Ryder, Sheila A. %A Khan, Denise %A Marquez, Juan F. %A Gilmer, John F. %D 2008 %J Journal of Medicinal Chemistry %K butyrylcholinesterase carbamate cholinesterase esters inhibitors isosorbide myown potent selective %N 20 %P 6400-6409 %R 10.1021/jm800564y %T Isosorbide-2-carbamate Esters: Potent and Selective Butyrylcholinesterase Inhibitors %U http://pubs.acs.org/doi/abs/10.1021/jm800564y %V 51 %X 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.

@article{doi:10.1021/jm800564y, abstract = {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. }, added-at = {2013-07-31T00:08:16.000+0200}, author = {Carolan, Ciaran G. and Dillon, Gerald P. and Gaynor, Joanne M. and Reidy, Sean and Ryder, Sheila A. and Khan, Denise and Marquez, Juan F. and Gilmer, John F.}, biburl = {https://www.bibsonomy.org/bibtex/26ce18a1c1720afa43af1c2c0ec2a803e/sryder}, doi = {10.1021/jm800564y}, eprint = {http://pubs.acs.org/doi/pdf/10.1021/jm800564y}, interhash = {a9fb5161c174696a46a94365a4cd0eb1}, intrahash = {6ce18a1c1720afa43af1c2c0ec2a803e}, journal = {Journal of Medicinal Chemistry}, keywords = {butyrylcholinesterase carbamate cholinesterase esters inhibitors isosorbide myown potent selective}, note = {PMID: 18817366}, number = 20, pages = {6400-6409}, timestamp = {2013-07-31T00:08:16.000+0200}, title = {Isosorbide-2-carbamate Esters: Potent and Selective Butyrylcholinesterase Inhibitors}, url = {http://pubs.acs.org/doi/abs/10.1021/jm800564y}, volume = 51, year = 2008 }