title: Isosorbide-based cholinesterase inhibitors; replacement of 5-ester groups leading to increased stability.
abstract: Isosorbide-2-carbamate-5-esters are highly potent and selective butyrylcholinesterase inhibitors with potential utility in the treatment of Alzheimer's Disease (AD). They are stable in human plasma but in mouse plasma they undergo hydrolysis at the 5-ester group potentially attenuating in vivo potency. In this paper we explore the role of the 5-position in modulating potency. The focus of the study was to increase metabolic stability while preserving potency and selectivity. Dicarbamates and 5-keto derivatives were markedly less potent than the ester class. The 2-benzylcarbamate-5-benzyl ether was found to be potent (IC(50) 52 nM) and stable in the presence of mouse plasma and liver homogenate. The compound produces sustained moderate inhibition of mouse butyrylcholinesterase at 1mg/kg, IP.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Dillon
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Gaynor
authors.forename: Denise
authors.initials: D
authors.lastname: Khan
authors.forename: Ciaran G
authors.initials: CG
authors.lastname: Carolan
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Ryder
authors.forename: Juan F
authors.initials: JF
authors.lastname: Marquez
authors.forename: Sean
authors.initials: S
authors.lastname: Reidy
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007547:Isosorbide / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010949:Plasma / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D002091:Butyrylcholinesterase; D007547:Isosorbide