%0 Journal Article %1 doi:10.1021/jm9014845 %A Carolan, Ciaran G. %A Dillon, Gerald P. %A Khan, Denise %A Ryder, Sheila A. %A Gaynor, Joanne M. %A Reidy, Sean %A Marquez, Juan F. %A Jones, Mike %A Holland, Valerie %A Gilmer, John F. %D 2010 %J Journal of Medicinal Chemistry %K aspirin butyrylcholinesterase carbamate inhibitor isosorbide myown potent prodrug pseudosubstrate selective %N 3 %P 1190-1199 %R 10.1021/jm9014845 %T Isosorbide-2-benzyl Carbamate-5-salicylate, A Peripheral Anionic Site Binding Subnanomolar Selective Butyrylcholinesterase Inhibitor %U http://pubs.acs.org/doi/abs/10.1021/jm9014845 %V 53 %X Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.

@article{doi:10.1021/jm9014845, abstract = {Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site. }, added-at = {2013-07-31T00:36:20.000+0200}, author = {Carolan, Ciaran G. and Dillon, Gerald P. and Khan, Denise and Ryder, Sheila A. and Gaynor, Joanne M. and Reidy, Sean and Marquez, Juan F. and Jones, Mike and Holland, Valerie and Gilmer, John F.}, biburl = {https://www.bibsonomy.org/bibtex/27d0f945b48f0f9f0f492e71a76910a5e/sryder}, doi = {10.1021/jm9014845}, eprint = {http://pubs.acs.org/doi/pdf/10.1021/jm9014845}, interhash = {e2a5ce26aaa09706899ddcc1445ed81a}, intrahash = {7d0f945b48f0f9f0f492e71a76910a5e}, journal = {Journal of Medicinal Chemistry}, keywords = {aspirin butyrylcholinesterase carbamate inhibitor isosorbide myown potent prodrug pseudosubstrate selective}, note = {PMID: 20067290}, number = 3, pages = {1190-1199}, timestamp = {2013-07-31T00:36:20.000+0200}, title = {Isosorbide-2-benzyl Carbamate-5-salicylate, A Peripheral Anionic Site Binding Subnanomolar Selective Butyrylcholinesterase Inhibitor}, url = {http://pubs.acs.org/doi/abs/10.1021/jm9014845}, volume = 53, year = 2010 }