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Isosorbide-based cholinesterase inhibitors; replacement of 5-ester groups leading to increased stability
RYDER, SHEILA
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 (IC50 52 nM) and stable in the presence of mouse plasma and liver homogenate. The compound produces sustained moderate inhibition of mouse butyrylcholinesterase at 1 mg/kg, IP.
Keyword(s): Butyrylcholinesterase inhibitor; Selectivity; Metabolic stability; Butyrylcholinesterase; Inhibitors; Enzyme inhibitors; Cholinesterase inhibitors; Drug stability; Stability; Neuroscience
Publication Date:
2010
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: Trinity College Dublin
Citation(s): Dillon GP, Gaynor JM, Khan D, Carolan CG, Ryder SA, Marquez JF, Reidy S, Gilmer JF, Isosorbide-based cholinesterase inhibitors; replacement of 5-ester groups leading to increased stability, Bioorg Med Chem, 18, 3, 2010, 1045 - 1053
First Indexed: 2014-05-13 05:22:45 Last Updated: 2017-12-17 06:16:55