Classics in Chemical Neuroscience: Donepezil - ACS Publications

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Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX

Classics in Chemical Neuroscience: Donepezil James T. Brewster II,† Simone Dell’Acqua,*,‡ Danny Q. Thach,§ and Jonathan L. Sessler*,† †

Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, United States Department of Chemistry, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy § Department of Chemistry, University of CaliforniaBerkeley, Berkeley, California 94720, United States

ACS Chem. Neurosci. Downloaded from pubs.acs.org by UNIV OF RHODE ISLAND on 11/30/18. For personal use only.

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ABSTRACT: The discovery of acetylcholine and acetylcholinesterase provided the first insight into the intricacies of chemical signal transduction and neuronal communication. Further elucidation of the underlying mechanisms led to an attendant leveraging of this knowledge via the synthesis of new therapeutics designed to control aberrant biochemical processes. The central role of the cholinergic system within human memory and learning, as well as its implication in Alzheimer’s disease, has made it a point of focus within the neuropharmacology and medicinal chemistry communities. This review is focused on donepezil and covers the background, synthetic routes, structure−activity relationships, binding interactions with acetylcholinesterase, pharmacokinetics and metabolism, efficacy, adverse effects, and historical importance of this leading therapeutic in the treatment of Alzheimer’s disease and true Classic in Chemical Neuroscience. KEYWORDS: Donepezil, cholinergic hypothesis, acetylcholinesterase inhibitor, Alzheimer’s disease, neurodegeneration, Classics in Chemical Neuroscience

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INTRODUCTION Central nervous system (CNS) neurodegeneration is defined by the loss of structure and function followed by the death of neurons in the brain and spinal cord.1−3 Clinical symptoms associated with such disease states manifest through numerous pathways and are classified as ataxias, loss of body movement, or dementias, impaired mental processes.4,5 However, the complex etiology of CNS neurodegenerative disorders often results in comorbid health problems, further complicating treatment protocols.6−9 Alzheimer’s disease (AD) is one of the most common dementias, comprising more than 80% of all cases. It affects nearly 40 million people worldwide with an associated health care cost of approximately $820 billion per year.10,11 This sum does not include the emotional impact on family and caregivers. AD is a progressive illness correlated with the accumulation of extracellular amyloid plaques and intraneuronal tau neurofibrillary tangles (NFTs), increased oxidative and nitrosative damage, as well as impaired glucose metabolism, among other symptoms.12,13 The clinical phenotype includes a long preclinical and prodromal phase spanning between 5 and 20 years followed by a clinical period of 8−10 years. Over the course of this disease, patients undergo loss of short- and long-term memory as well as reduction in the ability to concentrate and learn or retain new information.14 Therapeutic efforts toward treating this disease have focused on delaying the progression of cognitive and noncognitive symptoms.15,16 Attempts to dissect the pathophysiological processes of AD have focused on abnormalities related to amyloid beta (Aβ), tau proteins, neuroinflammation, and the cholinergic system.17−21 Of these, the cholinergic hypothesis has been validated as a clinically viable target.22−26 © XXXX American Chemical Society

Postmortem analysis of AD brain tissue typically reveals damage and abnormalities within the basal and rostral cholinergic systems.27−30 The relationship between loss of cholinergic brain neurons and a decrease in awareness, attention, learning, sleep, and working memory has led to attempts at therapeutic intervention via the cholinergic pathway.31,32 A direct outshoot of these efforts was the discovery of acetylcholinesterase inhibitors (AChEIs). Several were found to serve as clinically effective cholinergic replacements and have seen extensive use in treating cognitive dysfunction associated with AD (Figure 1).

Figure 1. Representative therapeutics for the treatment of AD. Current approved drugs include: donepezil (Aricept), galantamine (Razadyne), memantine HCl (Namenda), rivastigmine (Exelon), and donepezil + memantine HCl (Namzaric). Received: September 28, 2018 Accepted: October 29, 2018 Published: October 29, 2018 A

DOI: 10.1021/acschemneuro.8b00517 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX

Review

ACS Chemical Neuroscience Donepezil (E-2020, Aricept) is one of five approved and widely prescribed therapeutics for addressing global clinical function and the cognitive deficits of mild to moderate AD.33−37 It is a piperidine-based reversible inhibitor displaying noncompetitive activity with limited competitive action.38−40 Interestingly, donepezil acts on acetylcholinesterase and has only a modest effect on butyrylcholinesterase; this stands in contrast to the dual activity seen for other agents (e.g., rivastigmine and tacrine).41,42 Due to its favorable therapeutic profile, donepezil is often considered the first-line treatment in patients with mild to moderate AD.43−46 Here, we present a detailed review on the chemistry, pharmacology, and importance of donepezil in neuropharmacology and the treatment of Alzheimer’s disease.

steps. The indanon-2-ylidenyl piperidine (5) was prepared by first subjecting 5,6-dimethoxyl-1-indanone (4) to deprotonation with lithium diisopropylamide (LDA) in the presence of hexamethyl-phophoric amide (HMPA) at −78 °C for 15 min. Compound 3 was added, and the mixture was warmed to room temperature and then stirred for 2 h. After workup and purification, 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl-methylpiperidine hydrochloride (5) was isolated in 62% yield. Reduction with H2 in the presence of 5% Pd/C in tetrahydrofuran (THF) at room temperature for 6 h, followed by purification, preparation of the HCl salt, and recrystallization gave donepezil HCl as a racemate (R,S) in 82% yield (9.1% overall yield). Alternative routes for the preparation of donepezil are known. These include the synthesis of pyridinium (6) or pyridine intermediates via alkylation or aldol reaction followed by benzylation and reduction (pyridinium) or reduction and benzylation (pyridine) to give donepezil HCl in 50.8−82% overall yield (Scheme 2a).57−59 Late stage construction of the

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CHEMICAL PROPERTIES AND SYNTHESIS Donepezil (CAS number 120014-06-4, IUPAC name 2-((1benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1Hinden-1-one; donepezil HCl: CAS number 120011-70-3) is a low molecular weight (MW = 379.50 or 415.96 as the monoHCl salt) piperidine-based dihydro-1-indenone that is used as a racemic mixture (R,S) of two possible stereoisomers. Its empirical formula is C24H29NO3 or C24H29NO3 HCl for the HCl salt. Donepezil HCl, also known by the trade name Aricept and Aricept ODT, has a melting point of 211−212 °C47 and is soluble in water, DMSO, and glacial acetic acid, slightly soluble in ethanol and acetonitrile, and is practically insoluble in ethyl acetate or n-hexane.48 The free base has a LogP of 3.08−4.1149 (3.6)50 and cLogP of 4.6051 (4.2).52 Considered in light of Lipinski’s rules,53−55 it is worth noting that donepezil has zero hydrogen bond donors, four hydrogen bond acceptors, six rotatable bonds, and a topological polar surface area of 38.8 Å2. The original synthesis of donepezil was reported in a patent assigned to Eisai Co., Ltd. describing a general route toward cyclic amines with anticholinesterase activity (Scheme 1).56

Scheme 2. (a) Convergent Preparation of Pyridinium Intermediates and (b) Synthesis of Indenone Core en Route to Donepezil

1-indenone core from enone 7, followed by subsequent transformation, has also been used to give donepezil HCl in 19.3% overall yield (Scheme 2b).60 Numerous other methods have also been developed.61−65 As a direct extension of these efforts, the synthesis of 11C, 14 C, and 18F radiolabeled versions of donepezil have been described.66−68

Scheme 1. Synthetic Route Used by Eisai Co., Ltd. (1987) to Obtain Donepezil

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MANUFACTURING INFORMATION Donepezil was initially manufactured and comarketed by Eisai Co., Ltd. (4523.T) and Pfizer Inc. (PFE.N).69 More recently, donepezil has been marketed by Actavis/Allergan as Namzaric, a combination pill comprised of memantine HCl (28 mg) and donepezil (10 mg), as well as in generic prescription products by Teva Pharmaceutical Industries Ltd., Accel Pharma Inc., Lupin Pharmaceutical Inc. (LPI), Auro Pharma Inc., and Apotex, among others.70,71 Donepezil is currently prescribed as 5, 10, or 23 mg immediate release formulations (Aricept) as well as a 5 or 10 mg extended release formulations (Aricept ODT).71 The average yearly cost of donepezil in the United States has fallen in recent years from approximately $700072 in 1998 to just over $2000 in 2012.73,74 The combined yearly sales of donepezil reached a peak of $3.316 billion in 2010.75−78 Sales have declined since donepezil came off patent in November 2010. However, the FDA approval of a new 23 mg dose permitted Eisai a three-year extension (2010−2013). Donepezil remains widely prescribed and is still a key component in new therapeutic modalities such as Namzaric and Allergan’s CPC-201 (donepezil + solifenacin).79

Briefly, the (methoxymethyl)triphenylphophonium Wittig (1) reagent was formed by deprotonation with n-butyl lithium (nBuLi). 1-Benzyl-4-piperidone (2) was then added, and the mixture was stirred at room temperature for 3 h. The resultant methyl enol ether was purified by silica gel chromatography then dissolved in 1 N HCl and refluxed for 3 h to give 1benzyl-4-piperidinecarboaldehyde (3) in 18% yield over two B


Review

ACS Chemical Neuroscience

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STRUCTURE−ACTIVITY RELATIONSHIP In a series of publications following the patent, Sugimoto and coworkers from Eisai Co., Ltd. disclosed the structure−activity relationship (SAR) work leading to donepezil. The development of donepezil can be traced to benzyl piperidine (10) (IC50 560 nM), a compound first discovered to possess antiAChE activity through random screening.80,81 Compound 10 was initially prepared using a synthetic route that started with the lithium aluminum hydride (LiAlH4) mediated reduction of piperidine 8 in diethyl ether (Et2O); this gave the ethyleneaminopiperidine 9 in 91.1% yield. Compound 9 was acetylated with benzoyl chloride, furnishing benzyl piperidine 10 in 65% yield (Scheme 3). Scheme 3. Eisai’s Synthesis of Benzyl Piperidine 3

Figure 2. Representative heterobicyclic benzylpiperidine AChE inhibitors.

lacking aromatic bicycles, such as valerolactam (20) (IC50 270 nM), proved less active. In a continuation of this work, Sugimoto and coworkers extended the isoindolin-1-one and phthalimide series to indenone-based compounds (Figure 3).41 Initial studies led

Structure−activity relationship studies on the benzyl piperidine core focused on four regions, the (i) benzoyl functionality, (ii) amide moiety, (iii) piperidine ring, and (iv) piperidine-N-benzyl group. Through these efforts, it was discovered that the benzoyl group was amenable to modification with substitution in the meta- and para-position improving inhibition (producing IC50 values ranging from 29 to 470 nM). Bulky and lipophilic moieties (e.g., methyl ketone; IC50 51 nM, and benzyl sulfone; IC50 29 nM) in the paraposition were particularly effective. Converting the benzoyl formally to either nicotinamide or isonicotinamide (3- or 4substituted pyridine) also improved inhibition. On the other hand, saturating the aryl to give cyclohexanecarboxamide led to decreased activity (IC50 1600 nM). For the N-amide functionality, lower alkyls, methyl (11) or ethyl (12), and phenyl (13), could be added to improve inhibition, with IC50 values of 130, 170, and 35 nM being seen for the methyl, ethyl, and phenyl derivatives, respectively. Modifications of the piperidine and benzyl substituent served to confirm the importance of the piperidine nitrogen basicity as well as specific benefits of the benzyl moiety. Indeed, most changes to these two subunits greatly reduced activity. Building off these efforts, Sugimoto and coworkers expanded the SAR studies to include more rigid systems, including isoindolin-1-one, phthalimide, and other heterobicyclic ring structures (Figure 2).82 Interestingly, in comparison to the Nmethyl benzoyl derivative described in the first publication (IC50 170 nM), the isoindolin-1-one analogue (14) was approximately 2-fold more potent (IC50 98 nM). Addition of another carbonyl functionality produce phthalimide 15 that approximately 6-fold more potent (IC50 30 nM). Further elaboration of the phthalimide core also demonstrated that the aromatic subunit could be functionalized to increase activity. The six-membered ring derivatives generally proved less potent and only the quinazoline-2,4-dione (16) (IC50 4.2 nM), 1,4dihydroisoquinolin-3-one (17) (IC50 17 nM), and 3,4dihydroquinazolin-2-one (18) (IC50 13 nM) or direct structural analogues had improved activity. Reduced substrates, such as tetrahydroisoquinoline (19) (IC50 1600 nM), or those

Figure 3. Iterative SAR sequence that led to the development of donepezil.

to the conclusion that loss of the amide nitrogen in isoindolin1-one (14) (as seen in indenone 21) gave rise to only a slight reduction in potency. Further SAR studies focused again on modification of the four parts: (i) indenone, (ii) alkyl linker between the indenone and piperidine, (iii) piperidine, and (iv) piperidine-N-benzyl substituent. The compounds synthesized in the context of these SAR studies were analyzed in the form of a racemic mixture. Changing the alkyl linker to propylene (22) (IC50 1.5 nM) enhanced activity. An activity order of propylene (22) (IC50 1.5 nM) > methylene (23) (IC50 5.7 nM) > pentylene (24) (IC50 14 nM) > ethylene (21) (IC50 30 nM) > butylene (25) (IC50 35 nM) was found. An (E)-exo-methylene double bond derivative (26) (IC50 13 nm) displayed lower activity compared to that of the saturated methylene. Compound 22 C


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ACS Chemical Neuroscience was used as the lead compound for ensuing SAR studies. Modification of the indenone (5-membered ring) to a larger αtetralone (27) (6-membered ring) or 1-benzosuberanone (28) (7-membered ring) resulted in diminished activities of IC50 2100 and 15000 nM for 27 and 28, respectively (Figure 4).

Figure 5. KBIs for donepezil within AChE as inferred from X-ray structural analyses.

Figure 4. SAR studies centered around the inden-1-one core.

Reduction of the indenone carbonyl to the alcohol (IC50 300 nM) and elimination (IC50 4400 nM) led to the conclusion that this functional group plays a role in mediating the antiAChE activity. Computational and X-ray crystallographic analyses confirmed this observation. Similar to the SAR centered on the benzyl piperidine 10, the piperidine and benzyl group in 22 were not amenable to modification without lowering activity. Previous work on the phthalimide derivative showed improved activity with modification to the benzene subunit. The addition of methoxy substituents to the 5- and 6positions of the indenone core imparted a more than 25-fold increase in activity (IC50 5.7 nM). This final compound became donepezil. Pharmacological studies on each enantiomer showed (R)-donepezil (IC50 3.35 nM) as being approximately 5-fold more active than (S)-donepezil (IC50 17.5 nM).42 Simulated binding studies in tandem with structural analysis of the Torpedo californica (electric eel) acetylcholinesterase (TcAChE)−donepezil complex have provided insight into the binding mode of benzylpiperidine acetylcholinesterase inhibitors.41,42,83−85 An in-depth analysis of the key binding interactions (KBIs) between donepezil and the TcAChE active site came from the X-ray crystal structure of the (TcAChE)donepezil complex (2.5 Å).84 Of note is that even though the racemate (R,S)-donepezil was used to grow the crystal used for the structural analysis, only (R)-donepezil was found within the binding pocket. Nevertheless, the structure revealed the presence of multiple KBIs within the active-site gorge that provided support for the minimal discrimination between the two enantiomers (Figure 5).84 The most important interactions between TcAChE and donepezil were: In the so-called lower gorge, or anionic site, (a) the N-benzyl group participates in aromatic interactions with Trp84. Opposite this, (b) the benzyl group participates in an aromatic hydrogen bond with water held via hydrogen bonding interactions between two water molecules and the oxyanion hole (esteratic site) comprised of the peptidic NH protons from Gly118, Gly119, Gly201, and the oxygen of Ser200. Located in the middle of the active site gorge, (c) the piperidine participates in a cation−π interaction with Phe330.

The protonated piperidine also participates in (d) hydrogen bonding interactions with Tyr121 through a bridging water molecule. The entrance (top) of the active site also supports (e) aromatic interactions between Trp279 and the indenone core. It also allows for (f) hydrogen bonding between Glu185, a bridging water molecule, and the 5,6-dimethoxy functionality. The carbonyl of the indenone is proposed to help orient the substrate via edge-on van der Waals interactions involving donepezil and Phe331 and Phe290. This binding motif led to the suggestion that donepezil inhibits formation of the Michaelis complex (enzyme + substrate) or prevents deacylation of acetylcholine within the enzyme pocket.

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PHARMACOLOGY Pharmacological studies on the cholinergic system have provided insight into its importance in neurodegenerative pathways as well as the utility of acetylcholinesterase inhibitors in staving off cognitive and behavioral deficits.86−91 Acetylcholinesterases (AChEs) are α/β serine hydrolases predominantly found in the brain within cholinergic synapses. This enzyme has also been found throughout the central and peripheral nervous system; in nerve and muscle cells, on the membrane of red blood cells, and in motor, sensory, cholinergic, and noncholinergic fibers.96−98 AChE is responsible for terminating a nerve impulse via the hydrolysis of acetylcholine and returning the cell back to resting state after an action potential.92−95 Recent studies on AChEs have also located a peripheral binding site proposed to mediate the nonclassical activity (all other functions excluding the cleavage of acetylcholine into choline and acetate).107 Genomic data on AChEs across multiple species has provided assistance in elucidating its role in the enzymatic decomposition of acetylcholine throughout the body. The genetic information has also allowed for comparison of the amino acid constituents, giving insight into important sequence fragments and components of AChE (e.g., catalytic and structural subunits).93 AChE can exist in several oligomeric assembly modes with the tetrameric, G4 form, comprising most AChE constructs.86 The natural modification D


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In many cases, these therapeutics serve the dual purpose of also preventing the interaction of Aβ with the AChE peripheral anionic site. This latter effect has been shown to stave off damage to cholinergic neurons,110 as well as stop the nonclassical activity of AChE-promoted Aβ fibrillation and formation of cytotoxic AChE-Aβ complexes.111,112 Donepezil, in particular, modifies AD pathology by inducing changes in postsynaptic cell function through an increase in cerebral acetylcholine while engendering a concomitant decrease in AChE activity; it also blocks the peripheral anionic site and prevents Aβ-mediated damage.118,119 Donepezil has been noted to increase nicotinic ACh receptors in cortical neurons, while other processes related to ChAT, including vesicular ACh transport, HACU, and the action of muscarinic ACh receptors are not affected.120 Other actions of donepezil have been ascribed to its agonistic activity with, and high affinity for, the sigma-1 receptor (σ1R).121,122 The σ1Rs are ligand regulated, transmembrane molecular chaperones on the endoplasmic reticulum with several functions, such as regulating calcium homeostasis and cell growth as well as reducing oxidative stress. σ1R has been postulated as a potential therapeutic target for neurodegenerative disease.121 Donepezil has also been shown to induce reversible inhibition of voltage-activated sodium currents as well as delay rectifier and fast transient potassium currents through voltage-dependent and independent pathways, respectively.123 However, the concentrations used in the voltage-gated ion channel studies were higher than those considered clinically relevant in the case of AD patients.

of AChE within humans gives rise to AChE species able to carry out the requisite function in numerous systems (e.g., neurons, muscle cells, red blood cells, and various fibers). Systematic alterations are carried out by alternative mRNA splicing at the 5′ and 3′ ends. Changes to the 3′ end are responsible for the observed variations in AChE.99−103 The three main AChEs are synaptic (-S), erythrocytic (-E), and read-through (-R) AChE. AChE-R is typically monomeric and soluble. Depending upon the C-terminal sequence, the AChES and -E species can assemble into homologous AChE oligomers and heterologous species with noncatalytic subunits used to direct localization. AChE-S is typically covalently modified and attached to a hydrophobic subunit (P) or a polyproline sequence found within a collagen protein (T). The resulting bundling furnishes AChEs that are membrane bound.104,105 AChE-E is often found modified via transamidation that allows attachment of a glycophosphatidylinositol (PI) associated with the erythrocyte (red blood cell) surface.106 The catalytic mechanism of AChE involves an acetylenzyme mechanism wherein a catalytic trio comprised of serine (Ser200), histidine (His440), and an atypical glutamate (Glu327) serve to hydrolyze acetylcholine into choline and acetate.86,92,108,109 Presumably, this occurs via a general acid− base mechanism. The active site is comprised of 14 aromatic and an anionic residue that are believed to promote interactions with the quaternary ammonium of acetylcholine. Interestingly, despite such a deep active site gorge, AChE has high catalytic activity; it is capable of hydrolyzing approximately 25 000 molecules of acetylcholine per second.92,93 The mechanism of acetylcholine-mediated neuronal activation involves first the choline acetyltransferase (ChAT) mediated synthesis of acetylcholine (ACh) from choline and acetyl coenzyme A. ACh is then transported into synaptic vesicles by vesicular ACh transporters. Following an action potential and terminal depolarization, the vesicle fuses with the presynaptic membrane and releases ACh into the synaptic cleft. AChE hydrolyzes ACh, thus terminating the transmission, forming acetate and choline for future processes. The choline is returned to the presynaptic axon terminal (synaptic bouton) by a high-affinity choline uptake (HACU) transporter.113,114 Acetylcholine molecules interact with postsynaptic receptors to alter cellular function, either by altering ion flux across the membrane, as in the case of nicotinic ACh receptor activation,87,115 or through the generation of intracellular secondary messengers, as the result of muscarinic ACh receptor activation.116,117 By prolonging the lifetime of ACh within the synaptic cleft, cholinergic receptors undergo enhanced stimulation resulting in a concomitant modification in ACh-mediated downstream effects. The mechanism of action modulated through AChE is the same for therapeutics as for toxic alkaloids, pesticides, and chemical warfare agents.87−90 However, one difference lies in the mode of action. As a general rule, therapeutics induce reversible effects, whereas toxins typically produce irreversible changes in AChEs. Recent research on noncovalent, reversible inhibitors has led to the suggestion that the toxic side effects of many AChE inhibitors may reflect potent interactions with other protein and enzymatic processes (i.e., off-target effects).87−90 Therapeutic intervention via AChE has focused on the use of reversible inhibitors to increase the lifetime of acetylcholine.

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PHARMACOKINETICS AND DRUG METABOLISM Donepezil has an oral bioavailability of approximately 100% with absorption occurring via the intestinal tract.124,125 The maximum plasma concentration (Cmax), area under the plasma concentration−time curve (AUC), and the mean donepezil concentration at steady state are linearly proportional to dosage.124−126 The determination of donepezil plasma concentration has been used as a marker to trace its pharmacokinetics with liquid chromatography tandem mass spectrometry being the most exploited technique for such analysis.127,128 Capillary electrophoresis has also been used to provide insight into donepezil plasma concentrations.129 Within this latter context, most studies have indicated that the peak plasma concentration of donepezil is obtained within 3−4 h after oral administration. The use of 14C-radiolabeled donepezil has provided some insight into the drug concentrations in blood, brain compartments, and tissues after single-dose administration.130 A recent study has revealed that the donepezil concentration in cerebrospinal fluid is higher at 24 h after administration than at 12 h.131 However, information regarding donepezil metabolism in cerebral compartments remains scarce. Pharmacokinetic analysis of donepezil has demonstrated a slow clearance with a terminal elimination half-life of approximately 70 h.132 In the plasma, donepezil is bound to serum protein with approximately 93% being bound after single dose administration126 and 96% being bound after multiple doses.133 Donepezil is metabolized primarily in the liver with only 15% unmodified drug being recovered in urine.126−134 The predominant route for elimination is renal excretion. When accounting for the total amount administered (unchanged donepezil plus metabolites), 79% was found in urine and 21% in feces.134 The more recent 23 mg formulation E


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metabolic pathways combining two or more modifications, may also be operative.134 The most abundant metabolite, M1, has been proposed to have an activity similar to that of donepezil.146 The effects of age on the pharmacokinetics of donepezil have been tested by comparing the relative response of young and elderly healthy subjects.147 This study revealed that tmax and the plasma elimination half-life of the beta-phase (t1/2 beta) increase with age, whereas the maximum peak plasma concentration and AUC remain unchanged. Genetic analysis has revealed substantial variability in the clinical response to donepezil due to different pharmacokinetic and pharmacodynamic effects, mostly mediated by a CYP-2D6 based metabolism.148 Similar conclusions were drawn from a study with rats, which led to the inference that aging leads to an increase in the t1/2, mean residence time (MRT), and volume of distribution (Vd), whereas the AUC is maintained.149 Donepezil, as currently prescribed, is racemic. Therefore, characterization of the differences in metabolism, if any, for the two enantiomers is important in terms of assessing drug efficacy. Interestingly, the mean plasma levels of the less potent (S)-donepezil antipode (IC50 17.5 nm) are higher than those of its (R)-donepezil enantiomer (IC50 3.35 nm).150 In vitro microsomal systems and in vivo human studies have also demonstrated that (R)-donepezil is metabolized faster than (S)-donepezil.150,151

of donepezil, compared to the traditional 10 mg formulation, shows an increase in the maximum plasma concentration (Cmax) and in the time that the drug is present at the Cmax (tmax).135 This treatment is therefore proposed as a method for treating moderate-to-severe AD as opposed to the lower dose formulations that are used for early stage AD. After oral administration, the hepatic (liver) transformation of donepezil is catalyzed by cytochrome P450 (CYP) enzymes with isoenzymes CYP-2D6 and CYP-3A4 playing a major role.134 The slow metabolism of donepezil is consistent with the observed lack of appreciable pharmacokinetic interactions with other drugs that are metabolized by the same enzymes, such as warfarin,136 theophylline,137 cimetidine,138 and digoxin.139 However, the simultaneous administration of donepezil and ketoconazole, a potent CYP-3A4 inhibitor, leads to significantly higher donepezil plasma concentrations with potential adverse effects.140 Donepezil pharmacokinetic parameters are often not affected by coadministration of many other drugs, such as risperidone,141,142 setraline,143 and memantine, as demonstrated by the combination therapy Namzaric.144 On the other hand, administration of donepezil with levodopa leads to an increase of Cmax and tmax of levodopa. This suggests the potential for adverse effects when combing the two medications.145 Adverse drug−drug interactions are limited, but do exist. These are discussed further in the next section. There are currently three proposed metabolic pathways for donepezil:134 (i) O-dealkylation to the metabolites 6-Odesmethyl-donepezil (M1) and 5-O-desmethly-donepezil (M2), with partial subsequent glucuronidation to metabolites M11 and M12; (ii) formal N-dealkylation to metabolite M4; and (iii) N-oxidation to metabolite M6 (Figure 6). Additional metabolic pathways, such as hydroxylation of the phenyl ring (N-benzyl) followed by sulfonation, hydroxylation of the benzyl position adjacent to the indenone core, as well as mixed

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DOSAGE, EFFICACY, AND ADVERSE EFFECTS Donepezil is distributed as a film-coated orally disintegrating tablet (ODT) currently available at 5, 10, and 23 mg in packages of 30−90 tablets.152 Clinical studies probing the efficacy of donepezil demonstrated that dosages of 5−10 mg/ day and 10−23 mg/day were effective in improving cognition for mild-to-moderate and moderate-to-severe dementia caused by AD, respectively.153 Open-label trials have revealed that dose titration of donepezil is recommended as a way to limit adverse effects. Toward this end, the FDA recommends a starting dose of 5 mg/day in the evening for 4−6 weeks. The dosage may then be increased to 10 mg/day for at least 3 months before increasing to 23 mg/day.152 Recent studies have led to the consideration that taking donepezil immediately after breakfast, as well as at a lower doses and with slower increases in dose, may be advantageous for patients sensitive to AChEIs.154 Clinical studies have proven that donepezil is effective in addressing the cognitive deficits associated with AD. Indeed, since gaining FDA approval, donepezil has been valued as a viable treatment of mild to severe AD.151 Analysis of clinical results provided support for the contention that donepezil is statistically superior versus a placebo in terms of improvement of cognition, as measured by Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), and severe impairment battery (SIB). It also provides improvement as judged by the severity of behavioral symptoms, based on Behavioral Pathology in Alzheimer’s Disease (BEHAVE-AD).155 Studies have shown that patients taking donepezil with mild to moderate AD had elevated statistical improvement in ADAS-cog measures (3.2 points) relative to patients with early AD (2.3 points). While patients with moderate-to-severe AD had an SIB difference of 5.7 points relative to placebo, patients with severe AD saw a SIB difference of 4.3 points.155 However, donepezil has been described as a palliative treatment for this patient population as

Figure 6. Primary metabolic products from donepezil. F


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the cholinergic and dopaminergic systems.181 Not surprisingly, adverse reactions due to an increase in donepezil plasma concentration are also possible when prescribed with paroxetine or other selective serotonin reuptake inhibitors (SSRIs) that inhibit CYP2D6.182 These drug−drug interactions have been observed in only a limited number of patients but should be of note to medical professionals prescribing donepezil.

it provided no clear effect on (i) the quality of life (QoL) for patients with AD, (ii) its ability to improve behavioral symptoms, or (iii) alter the disease course. PET imaging analysis of AChE activity demonstrated that regiments of donepezil at 5 and 10 mg/day yield approximately 20−40% inhibition.156 The limited maximal effect at such doses, coupled with increased cholinergic deficits in later-stage AD patients and diminishing therapeutic benefits over time, led to considerations that increased dosages might prove beneficial.157 The sponsors of donepezil, Eisai, thus developed the 23 mg formulation and carried out a randomized, doubleblind study conducted at 219 sites with 1467 patients in Asia, Europe, Australia, North America, South Africa, and South America.159 This clinical trial compared the 23 mg/day higherdose formulation to the standard 10 mg/day dose. Interestingly, the SIB was shown to have an improvement by only 2.2 points on a 100-point scale. There were also differences noted in the change plus caregiver input (CIBIC +), but group differences were not significant. There were no differences in MMSE or on the ADCS scale. Patients on the 23 mg dose plan were also more likely to drop out, 30% versus 18% on 10 mg/day, as well as 3 times more likely to experience gastrointestinal side effects, 21% on 23 mg/day versus 5.9% on 10 mg/day. Based upon this data, two FDA reviewers recommended not approving donepezil 23 mg/day.158 However, overall a recommendation for approval was made. The limited benefits, increased side effects, and putative “evergreening” strategy associated with the higher dosage remain widely discussed.159−163 The oddity of the 23 mg/day formulation has also been mentioned and it has been suggested that such a dosage could not be duplicated by taking multiples of the standard 5 or 10 mg/day formulations. Despite this controversy, donepezil has also been the subject of clinical studies involving bipolar disorder,164 sleep apnea,165 autism,166 and schizophrenia.167 Donepezil has also been shown to improve cognitive function in patients with traumatic brain injury,168 Down’s syndrome,169 and Lewy body dementia.170 Interestingly, studies demonstrate that the use of memantine, a commonly prescribed AD treatment, in conjunction with donepezil has an additive beneficial effect on cognitive function relative to the individual monotherapies in question.171,172 Clinically limiting issues associated with donepezil treatment are generally associated with cholinergic adverse effects on the gastrointestinal or nervous system. Symptoms often subside after several days and are reversible upon lowing the dose or ceasing drug administration.173 The most common side effects are muscle fatigue, cramps, lower mean heart rate, nausea, diarrhea, dizziness, and insomnia. More extreme symptoms, such as convulsions,174 urinary incontinence,175 and rashes,176 remain limited. Overdoses on donepezil are possible and have resulted in nausea, vomiting, diarrhea, and bradycardia. These symptoms are also attributed to cholinergic effects.177,178 Several drug−drug interactions with donepezil have been noted. These include extrapyramidal effects when prescribed with risperidone due to a reputed imbalance in the cholinergic and dopaminergic systems179 The concurrent administration of risperidone and donepezil is still considered safe.141,142 Coadministration of neostigmine and donepezil is also believed capable of inducing a prolonged neuromuscular blockade during anesthesia.180 Parkinsonism has been noted when donepezil is taken concurrently with tiapride, presumably as the result of a pharmacodynamic interaction and imbalance in

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IMPORTANCE IN NEUROSCIENCE The discovery of chemical-mediated signal transduction as a means for cellular communication spawned a new era in pharmacology.183 This concept soon expanded to the use of small molecules, natural and synthetic, as a means to modulate biochemical processes. Early efforts by Sir Henry Dale and George Barger184 demonstrated that aliphatic, phenethyl, and phenylethyanolamines, many of which were discovered as constituents of putrid meat, could elicit an epinephrine-like (adrenaline) sympathomimetic action. These research pioneers also noted that hordenine methiodide and trimethylamineethylcatechol chloride (29), quaternary ammonium salts, induced a response indistinguishable from that of nicotine (Figure 7).

Figure 7. Representative synthetic and biogenic amines.

Concurrent with studies on the adrenergic system, Dale also led a research program exploring the properties of the rye fungus ergot. ACh could be isolated from the resulting extraction mixtures. Pharmacological analyses by Dale and Laidlaw served to demonstrate that ACh elicited a response similar to that produced by the alkaloids muscarine (muscarinic ACh receptors) and nicotine (nicotinic ACh receptors).184 Loewi continued these efforts and was able to demonstrate the communicative properties of vagusstoff between frog hearts in the same solution.185 This unidentified agent was later confirmed as acetylcholine. ACh was noted in these and other studies186 to have a short lifetime with rapid deactivation being seen in the presence of native aqueous organ extracts (e.g., heart extracts). The presence of cholinesterase was confirmed187 and established a role wherein a chemical transmitter induces downstream cellular responses that could be terminated by a natural enzymatic process.188−193 Through the decades, the cholinergic system has remained a focus in neuropharmacology and medicinal chemistry efforts.194,195 Its role in Alzheimer’s disease (i.e., the cholinergic hypothesis) has led to significant attempts at modulating various components of the ACh pathway. Within this paradigm, acetylcholine esterase inhibitors remain a mainstay in AD therapeutics and, of these, donepezil has proven a useful tool and viable treatment for AD patients.196−198 G


Review


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Donepezil truly represents a classic in chemical neuroscience. From a fundamental standpoint, it has provided insight into the key binding interactions and activity of AChE inhibitors. It has also helped elucidate so-called nonclassical mechanisms of AChE. In its direct application, donepezil has provided inspiration in the design of new AD therapeutics targeting related and new mechanisms (e.g., sigma-1 or preventing AChE mediated Aβ aggregation and AChE-Aβ complexes). Not surprisingly, donepezil continues to leave its mark in the annals of chemical neuroscience as it finds utility in combination therapies (e.g., in conjunction with Namzaric and CPC-201) and in the form of new drug conjugates.199−204

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

James T. Brewster, II: 0000-0002-4579-8074 Simone Dell’Acqua: 0000-0002-1231-4045 Jonathan L. Sessler: 0000-0002-9576-1325 Funding

This work was funded by the National Institutes of Health (Grant RGM103790 to J.L.S.) and the Robert A. Welch Foundation (Grant F-0018 to J.L.S.). S.D. would like to thank the Italian Ministry of Education, University and Research (MIUR) for a Research Project of National Interest (PRIN) 2015, Prot. 2015T778JW. J.T.B. would like to thank The University of Texas at Austin for the Stephen F. & Fay Evans Martin Presidential Fellowship in Chemistry and a Global Research Fellowship at The University of Pavia, Italy. D.Q.T would like to thank the NSF for a Graduate Research Fellowship. Notes

The authors declare no competing financial interest.

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