Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor.
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.
Carolan
Ciaran G
CG
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
Dillon
Gerald P
GP
Khan
Denise
D
Ryder
Sheila A
SA
Gaynor
Joanne M
JM
Reidy
Sean
S
Marquez
Juan F
JF
Jones
Mike
M
Holland
Valerie
V
Gilmer
John F
JF
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
D000838:Anions; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D012459:Salicylates; C547673:isosorbide-2-benzyl carbamate-5-salicylate; D002091:Butyrylcholinesterase; D007547:Isosorbide