Cholinesterase and carboxylesterase inhibitors as pharmacological agents

Аннотация

Literature data and authors’ own results on the role of serine hydrolases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as drug targets for treatment of neurodegenerative diseases and carboxylesterase (CaE) inhibitors as modulators of CaE-hydrolysis of ester-containing drugs are analyzed. Today, a promising approach is the development of cholinesterase inhibitors with additional neuroprotective and disease-modifying properties. The developed esterase profile approach, that is, comparative assessment of the inhibitory activity against AChE, BChE, and CaE, can be used to evaluate both the main potential pharmacological effect and possible side effects of a new compound. Analysis of the esterase profile, in combination with computer modeling and assessment of radical-scavenging ability of the synthesized compounds and their potential ability to block AChE-induced β-amyloid aggregation revealed highly active multifunctional compounds for the treatment of Alzheimer’s disease: selective inhibitors of BChE and inhibitors of both cholinesterases without potential side effects associated with CaE inhibition. A number of effective and selective inhibitors of CaE, free from cholinergic side effects, were also found for modulation of the rate of hydrolytic metabolism and for rational use of ester-containing drugs.