Isosorbide-2-benzyl Carbamate-5-salicylate, A Peripheral Anionic Site Binding Subnanomolar Selective Butyrylcholinesterase Inhibitor

Carolan, Ciaran; Dillon, Gerald Patrick; Khan, Denise; Ryder, Sheila A.; Gaynor, Joanne M.; Reidy, Sean; Marquez, Juan F.; Jones, Mike; Holland, Valerie; Gilmer, John F.

doi:10.1021/jm9014845

Cited by 55 publications

(46 citation statements)

References 33 publications

(73 reference statements)

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“…Although a number of structurally diverse selective reversible and pseudo-irreversible BChE inhibitors have been reported19202122232425, cymserine analogs are the only BChE inhibitors with reported in-vivo activity19, and one of them has successfully advanced to Phase I clinical trials: bisnorcymserine (Fig. 1a).…”

mentioning

confidence: 99%

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Košak¹,

Brus²,

Knez³

et al. 2016

Sci Rep

116

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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.

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mentioning

confidence: 99%

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Košak¹,

Brus²,

Knez³

et al. 2016

Sci Rep

116

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“…By varying the substituents on phenyl ring at C-5, the inhibitory profiles of (R,S)-24 and (R,S)-25 ( Fig. 11) surpassed that of the parent compound 23 (IC 50 ~ 0.2 and 1.2 nM; respectively) [51]. Furthermore, we recently developed a group of disubstituted pyrimidine derivatives with varying substituents at the C-2 and C-4 positions.…”

Section: Selective Buche Inhibitorsmentioning

confidence: 99%

Alzheimer's Disease: Emerging Trends in Small Molecule Therapies

Mohamed¹,

Rao²

2011

CMC

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Alzheimer's disease (AD) is a highly complex and rapidly progressive neurodegenerative disorder characterized by the systemic collapse of cognitive function and formation of dense amyloid plaques and neurofibrillary tangles. AD pathology is derived from the cholinergic, amyloid and tau hypotheses, respectively. Current pharmacotherapy with known anti-cholinesterases, such as Aricept® and Exelon®, only offer symptomatic relief without any disease-modifying effects. It is now clear that in order to prevent the rapid progression of AD, new therapeutic treatments should target multiple AD pathways as opposed to the traditional "one drug, one target" approach. This review will focus on the recent advances in medicinal chemistry aimed at the development of small molecule therapies that target various AD pathological routes such as the cholinesterases (AChE and BuChE), amyloidogenic secretases (β/γ- secretase), amyloid-β aggregation, tau phosphorylation and fibrillation and metal-ion redox/reactive oxygen species (ROS). Some notable ring templates will be discussed along with their structure-activity relationship (SAR) data and their multiple modes of action. These emerging trends signal a paradigm shift in anti-AD therapies aimed at the development of multifunctional small molecules as disease-modifying agents (DMAs).

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“…Over the past decades, numerous compounds have been synthesized and tested as cholinesterase inhibitors, including natural products and variants synthesized based on natural products [e.g., (Brus et al 2014; Huang et al 2013; Pinho et al 2013; Anand and Singh 2013; Carolan et al 2010; Kamal et al 2008)]. These classes of inhibitors include compounds that have been used as therapeutics, such as donepezil, galantamine, rivastigmine, and tacrine (Fig.…”

Section: Introductionmentioning

confidence: 99%

Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase

2016

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Cholinesterases are involved in neuronal signal transduction, and perturbation of function has been implicated in diseases, such as Alzheimer’s and Huntington’s disease. For the two major classes of cholinesterases, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), previous studies reported BChE activity is elevated in patients with Alzheimer’s disease, while AChE levels remain the same or decrease. Thus, the development of potent and specific inhibitors of BChE have received much attention as a potential therapeutic in the alleviation of neurodegenerative diseases. In this study, we evaluated amino acid analogs as selective inhibitors of BChE. Amino acid analogs bearing a 9-fluorenylmethyloxycarbonyl (Fmoc) group were tested, as the Fmoc group has structural resemblance to previously described inhibitors. We identified leucine, lysine, and tryptophan analogs bearing the Fmoc group as selective inhibitors of BChE. The Fmoc group contributed to inhibition, as analogs bearing a carboxybenzyl group showed ~tenfold higher values for the inhibition constant (KI value). Inclusion of a t-butoxycarbonyl on the side chain of Fmoc tryptophan led to an eightfold lower KI value compared to Fmoc tryptophan alone suggesting that modifications of the amino acid side chains may be designed to create inhibitors with higher affinity. Our results identify Fmoc-amino acids as a scaffold upon which to design BChE-specific inhibitors and provide the foundation for further experimental and computational studies to dissect the interactions that contribute to inhibitor binding.

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Isosorbide-2-benzyl Carbamate-5-salicylate, A Peripheral Anionic Site Binding Subnanomolar Selective Butyrylcholinesterase Inhibitor

Cited by 55 publications

References 33 publications

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Alzheimer's Disease: Emerging Trends in Small Molecule Therapies

Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase

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