title: Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor.
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.
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: Denise
authors.initials: D
authors.lastname: Khan
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Ryder
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Gaynor
authors.forename: Sean
authors.initials: S
authors.lastname: Reidy
authors.forename: Juan F
authors.initials: JF
authors.lastname: Marquez
authors.forename: Mike
authors.initials: M
authors.lastname: Jones
authors.forename: Valerie
authors.initials: V
authors.lastname: Holland
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D000838:Anions / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000097:blood / Q000737:chemistry* / Q000235:genetics; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007547:Isosorbide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D012459:Salicylates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000838:Anions; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D012459:Salicylates; C547673:isosorbide-2-benzyl carbamate-5-salicylate; D002091:Butyrylcholinesterase; D007547:Isosorbide