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. 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 IC 50 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.
Carolan
Ciaran G
CG
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
Dillon
Gerald P
GP
Gaynor
Joanne M
JM
Reidy
Sean
S
Ryder
Sheila A
SA
Khan
Denise
D
Marquez
Juan F
JF
Gilmer
John F
JF
D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002219:Carbamates / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007547:Isosorbide / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D004952:Esters; D002091:Butyrylcholinesterase; D007547:Isosorbide