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Title: Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer's disease Li Q, Yang H, Chen Y, Sun H Ref: Eur Journal of Medicinal Chemistry, 132:294, 2017 : PubMed
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders with notable factor of dysfunction in cholinergic system. Low ACh level can be observed in the pathogenesis of AD. Several AChE inhibitors have already been used for clinical treatments. However, other than normal conditions, ACh is mostly hydrolyzed by BuChE in progressed AD. Account for an increased level of BuChE and decreased level of AChE in the late stage of AD, development of selective BuChE inhibitor is of vital importance. Up till now, compounds with various scaffolds have been discovered to selectively inhibit BuChE. Different effective anti-BuChE molecules are concluded in this review.
The present study describes the synthesis, assessment of the anticholinesterase activity and the inhibition type of novel cis- and trans-3-arylaminocyclohexyl N,N-dimethylcarbamates. In vitro inhibition assay by Ellman's method with human blood samples showed that carbamates were selective for butyrylcholinesterase (BuChE) with compound concentration that inhibits 50% of enzyme activity (IC50) between 0.11 and 0.18 mmol L-1. cis- and trans-3-(4-Methoxyphenylamino) cyclohexyl N,N-dimethylcarbamate hydrochloride were the most active for BuChE, showing that the presence of methoxyl group enhanced the anticholinesterase activity. The enzyme kinetics studies indicate a noncompetitive inhibition against acetylcholinesterase (AChE) and mixed type inhibition for BuChE. Molecular modeling studies confirm the ability of carbamates to bind both the active and peripheral sites of the BuChE