Development of an in-vivo active reversible butyrylcholinesterase inhibitor.

Urban Košak,Martina Perše,Boris Brus,Simon Žakelj,Jurij Trontelj,Larisa Tratnjek,Barbara Malawska,Kinga Sałat,Xavier Brazzolotto,Barbara Filipek,Anja Pišlar,Stanislav Gobec,Damijan Knez,Roman Šink,Jasna Šlenc,Anna Więckowska,Martina Gobec,Florian Nachon,Jure Stojan,Adrian Podkowa,Nicolas Coquelle,Janko Kos,Marko Živin ,J.p Colletier ,Irena Mlinarič-Raščan

doi:10.1038/srep39495

Abstract

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

Highlights

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions
Our quest for novel sulfonamide BChE inhibitors began before the crystal structure of hit compound 1 in complex with human BChE (huBChE) was solved
The type I inhibitor was designed by replacing the carboxamide group of compound 1 with a sulfonamide group

Summary

Introduction

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Accumulation of amyloid βpeptide (Aβ) deposits[2,3], abnormal modification and accumulation of the protein tau[4] accompanied with oxidative stress in the brain lead to synaptic dysfunction and neurodegeneration[1] This most severely affects the cholinergic system[5] and results in a decrease in the levels of the neurotransmitter acetylcholine (ACh)[6], which in turn produces memory and cognitive deficits[7], characteristic for patients with AD. Three out of the four approved drugs for treatment of patients with AD are ChE inhibitors: the selective reversible AChE inhibitors donepezil[10] and galantamine[11], and the pseudo-irreversible dual ChE inhibitor rivastigmine[12] (Fig. 1a) These drugs exploit ChE inhibition to alleviate the symptoms of AD, or to temporarily slow down its progression, by restoring the cholinergic activity in the brain. The clinical efficacy of this drug class is mostly limited to mild and moderate stages of AD15,16

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Conclusion