title: Isosorbide-2-carbamate esters: potent and selective butyrylcholinesterase inhibitors.
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 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Ciaran G
authors.initials: CG
authors.lastname: Carolan
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Dillon
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Gaynor
authors.forename: Sean
authors.initials: S
authors.lastname: Reidy
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Ryder
authors.forename: Denise
authors.initials: D
authors.lastname: Khan
authors.forename: Juan F
authors.initials: JF
authors.lastname: Marquez
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: 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
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D004952:Esters; D002091:Butyrylcholinesterase; D007547:Isosorbide