title: Recent advances in acetylcholinesterase Inhibitors and Reactivators: an update on the patent literature (2012-2015).
abstract: Acetylcholinesterase (AChE) is the major enzyme that hydrolyzes acetylcholine, a key neurotransmitter for synaptic transmission, into acetic acid and choline. Mild inhibition of AChE has been shown to have therapeutic relevance in Alzheimer's disease (AD), myasthenia gravis, and glaucoma among others. In contrast, strong inhibition of AChE can lead to cholinergic poisoning. To combat this, AChE reactivators have to be developed to remove the offending AChE inhibitor, restoring acetylcholine levels to normal. Areas covered: This article covers recent advances in the development of acetylcholinesterase modulators, including both inhibitors of acetylcholinesterase for the efforts in development of new chemical entities for treatment of AD, as well as re-activators for resurrection of organophosphate bound acetylcholinesterase. Expert opinion: Over the past three years, research efforts have continued to identify novel small molecules as AChE inhibitors for both CNS and peripheral diseases. The more recent patent activity has focused on three AChE ligand design areas: derivatives of known AChE ligands, natural product based scaffolds and multifunctional ligands, all of which have produced some unique chemical matter with AChE inhibition activities in the mid picomolar to low micromolar ranges. New AChE inhibitors with polypharmacology or dual inhibitory activity have also emerged as highlighted by new AChE inhibitors with dual activity at L-type calcium channels, GSK-3, BACE1 and H3, although most only show low micromolar activity, thus further research is warranted. New small molecule reactivators of organophosphate-inhibited AChE have also been disclosed, which focused on the design of neutral ligands with improved pharmaceutical properties and blood-brain barrier (BBB) penetration. Gratifyingly, some research in this area is moving away from the traditional quaternary pyridinium oximes AChE reactivators, while still employing the necessary reactivation group (oximes). However, selectivity over inhibition of native AChE enzyme, effectiveness of reactivation, broad-spectrum reactivation against multiple organophosphates and reactivation of aged-enzyme continue to be hurdles for this area of research.
authors.affiliation: a Center for Innovative Drug Discovery, Department of Chemistry , University of Texas San Antonio, One UTSA Circle , San Antonio , TX , USA.
authors.forename: Stanton F
authors.initials: SF
authors.lastname: McHardy
authors.affiliation: a Center for Innovative Drug Discovery, Department of Chemistry , University of Texas San Antonio, One UTSA Circle , San Antonio , TX , USA.
authors.forename: Hua-Yu Leo
authors.initials: HL
authors.lastname: Wang
authors.affiliation: a Center for Innovative Drug Discovery, Department of Chemistry , University of Texas San Antonio, One UTSA Circle , San Antonio , TX , USA.
authors.forename: Shelby V
authors.initials: SV
authors.lastname: McCowen
authors.affiliation: a Center for Innovative Drug Discovery, Department of Chemistry , University of Texas San Antonio, One UTSA Circle , San Antonio , TX , USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Valdez
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D005901:Glaucoma / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D008024:Ligands; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000503:physiopathology; D010330:Patents as Topic
chemical_list: D002800:Cholinesterase Inhibitors; D008024:Ligands; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Alzheimer’s disease; acetylcholine; acetylcholinesterase re-activator; donepezil; echothiophate; galantamine; huperzine; metrifonate; multitarget directed ligands; oximes; physostigmine; rivastigmine; tacrine