donepezil hydrochloride

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This article describes the discovery processes of donepezil hydrochloride which is inhibitor of acetylcholinesterase enzyme. Cholinergic hypothesis and other studies proved that deterioration in cognitive functions in Alzheimer disease is due to deficit in cholinergic neurotransmission and target to treat Alzheimer disease is to inhibit acetylcholinesterase enzyme. Position emission tomography (PET) study has shown that donepezil distributes in all acetylcholineterase rich brain regions and binds to it. Structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) has also revealed that donepezil hydrochloride is gives optimum actylcholinesterase inhibition activity than its other analogues. Many methods are available for synthesis of donepezil hydrochloride with their merits and demerits.


Donepezil hydrochloride, Aricept, acetylcholinesterase inhibitors, PET study, indanone derivatives.

Abbrevations -

AD(Alzheimer disease), PET(position emission tomography), QSAR(quantitative structure activity relationship), Acetylcholinesterase inhibitor(AchEI),

Aim -

To study different processes involved in drug discovery of Donepezil hydrochloride.


The main Objectives of this project are given below

To study overall literature review of donepezil hydrochloride .

To discuss discovery process involved in discovery of donepezil hydrochloride such as target identification, target validation and lead optimization


Donepezil hydrochloride is the reversible acetylcholinesterase enzyme inhibitor having N-benzylpiperidine and indanone moiety in it (Sugimoto Hachiro et al, 2008). It is referred as E2020 in most of the pharmaceutical literatures. This is the second drug approved by U.S FDA for treatement mild and moderate Alzheimer disease (Stahl Stephen M et al, 2006). It is Patented and marketed in United states of America, some European and Asian countries under the trade name Aricept by,Ltd (Stahl Stephen M et al, 2006) (Tripathi KD , 2006) (Dale Rang H et al, 2006).

Drug Discovery of donepezil-

The drug discovery process of donepezil involves various phases as follows

Target identification

Target validation

Lead recognition

Lead optimization

Target identification-----

Target identification of drug means molecular recognition of site to which it will bind. For many drugs target is protein molecules. Target identification needs information about pathophysiology of disease and identification of particular biochemical steps that leads to therapeutic intervention. Conventional stratergies of target identification are mainly based on pathphysiology of disease. But newer stratergies of target of identification are based on proteonomics and genomics (Rang H PB et al, 2006). About 50-60% of Alzheimer disease patient are of over 65 year age (Sugimoto Hachiro et al, 2006). It is the neurodegenerative disorder with mean duration of 8.5 years between onset of action and death of patient (Sugimoto Hachiro et al, 2006). Symtoms of this disease includes gross and progressive impairement of cognitive functions. The most affected areas in the alzheimer's disease are hippocampus and neocortex which are important for mental functions. Pathophysiology of disease consists of external deposits of amyloid precursors and intracellular formation of neurofibrillary tangles leads to neuronal synapses loss (Francis Paul T et al, 1999)

Beta amyloid is the main component of sensile plaque formed by proteolysis of amyloid precursor proteins. Tangles are abnormally hyperphosphorylated tau proteins and regulated by balance between multiple kinases and phosphates. Hyperphosphorylation of tau proteins carry out sequestration of normal tau and other microtubule associated protein leads to impairment of axonal transport. This tau becomes prone to aggregation into insoluble fibril in tangles (Bartonili Manuala et al, 2003) (Andrisano Vincenza et al, 2003)

According to cholinergic hypothesis, deterioration in cognitive functions in Alzheimer disease is due to degeneration of cholinergic neuron into forebrain and consequently decreased cholinergic neurotransmission in cerebral cortex and hippocampus (Francis Paul T et al 1999).

Cholinergic neuron synthesizes acetylcholine, which is the acetic acid ester of choline. Acetylcholine is synthesized from the acetic acid and choline with the help of cholineacetylase. After stimuli vesicles discharge acetylcholine at the nerve ending and binds to postsynaptic receptors. Acetylcholine is stored into the synaptic vesicles which are accumulated at the nerve endings, also prevents its hydrolysis. Acetylcholine is hydrolises by acetylcholinesterase into acetic acid and choline(Tripathi KD 2006). Thus in Alzheimer disease cholinergic neurotransmission can be enhanced by inhibiting preventing the hydrolysis of acetylcholine, choline precursor,acetylcholine release facilitators ,M1 and M3 agonists ,Nicotinic agonistics but all these drugs were not effective to improve cognitive function in Alzheimer disease except cholinesterase inhibitors. Cholinesterase drugs have shown significant improvement in cognitive functions of Alzheimer disease. This has proved that cholinesterase inhibition is the main target to improve cognitive functions in Alzheimer disease (Sabbagha Marwan N et al, 2008) (Fisher Abraham et al, 2008).

Target validation of donepezil-

Target validation is the investigational approach by which potential drug target can be tested and given further reliability. Target validation is pharmaceutical approach in which influence of drug is observed. (Rang H PB et al, 2006). According to cholinergic and other studies acetylcholinesterase inhibition is the main target to improve imrove cogntitive functions in alzheimer disease patient. Okamaru Nobuyuki et al studied invivo binding of donepezil in the brain of alzheimer disease patient. They radiolabled donepezil as [11c-methoxy]-donepezil for position emission tomography imaging. Evaluation of binding and distribution of donepezil performed on mild and moderate Alzheimer disease patients. Normal control group volunteers had neither cognitive function impairements nor cerebrovascular lesions on magnetic resonance. PET study carried out after three months of neuropsychological medical examination. Region of interest analysis was carried for validation of regional distrubution of donepezil. PET images demonstrated that high volume of [11C]-donepezil distributed in all regions of brain like striatum, thalamus, striatum, and neocortex which are rich in acetylcholinesterase. Tissue time curves of [c11] -donipezil shown initial rapid uptake of donepezil in brain followed by gradual clearance in both elderly normal and alzheimer disease patients. Specific distribution volume was calculated from region of interest by metabolite - corrected plasma time activity curve. Donezpezil shown linear regression on logan plot analysis in all brain region as shown in figure -1. (Okamura Nobuyuki et al, 2008) (Yanai Kazuhiko et al, 2003)

Lead generation -

A lead compound is a new chemical entity that could potentialy developed into new drug by optimizing its valuable and minimizing side effect. High throught screening is mainly used for lead generation(Rang H P et al, 2006). Many drugs were trialed to improve the cognitive functions in Alzheimer disease like cholinergic agonist such as oxetremorine, choline precursor phosphatidylcholine but that were inffective. Numerous clinical trials carried out on acetylcholinesterase inhibitors such as physostigmine, this trial shown that this class of drug resulted in improvement of cognitive functions in Alzheimer disease patients. However these clinical trials also proved that physostigmine has poor brain Penetration and thus less active (Muramoto,M et al, 1979). In 1981 summers gave intravenous injection of tacrine to Alzheimer disease patients which were until that time used as antiseptic. These doses of tacrine shown measurable improvement in alzheimer symtoms but tacrine had shown many side effects such as hepatotoxicity( Farlow SI et al, 1992).

Later then scientist focused on development of new acetylcholinesterase inhibitors. Research and development of donepezil started in 1983 in Eisai .co .Ltd. Kawakami et al started to develop nontoxic tacrine derivatives but they failed to develop such tacrine derivative. While random screening scientists observed that N-benzylpiperazine (compound-A) has moderate anticholinesterase activity which was previously being synthesized for antiarterial sclerosis(Kawakami Yoshiyuki et al 2000)). During subsequent screening Kawakami et al used benzylpiperazine as seed compound and synthesized around 700 derivatives. Succeeding this experiment, it was observed that increase in acetylcholinesterase activity by replacing n-benzylpiperazine with N-benzylpiperidine moiety(compound-B). It was also found that slightly increase in activity by replacing ether group with amide group(compound-C) and removal of nitro group from benzamide moeity (compound-D) decreases activity. ((Kawakami Yoshiyuki et al 2000).

From these results Kawakami et al synthesized benzsulfonyl derivative and found that it is a most potent acetylcholinesterase inhibitor than benzpiperazine derivative. Benzsulfonyl derivarive showed very selective activity towards acetylcholinesterase but very poor bioavaibility. On the basis of this result they used benzoylsulfonyl derivative as lead compound. In next screening they replaced amide moiety with ketone moiety and maintained activity. Then Kawakami et al synthesized various indanone derivatives among them he found that donepezil has good acetylcholinesterase activity and bioavaibility(Sugimoto Hachiro et al, 1992).


Indananone derivatives were tested on rat for acetylcholinesterase inhibition activity according to method of Ellman et al. donepezil structure is divided into four rings as follows.

Part 1- Indanone ring

Part 2 -linkage moeity

Part 3- piperidine moeity

Part4 -benzyl moiety

Modification at Indanone moeity -

If indanone moeity is replaced with α-tetralone ,1-benzene suberone , 5,6 dimethoxy indene greately decreased activity ,while 25 fold increased activity by introducing methxy group at 5,6 position of indanone moeity .Carbonyl group is important for activity.Introduction of methoxy group at R3 position increase in activity by 20 fold .A methoxy group at R4 position increases activityby 10 fold . also slightly increase in activity on substitution to of methoxy group at para position in the benzoyl group moeity enhanced binding to the active site of acetylcholinesterase enzyme(Camps Pelayo et al, 2008).

2) Modification at linkage moiety-

Various bridging group between indanone and piperidine moeity were tested for cholinesterase activity. If both indanone and piperidine rings joined directly then it dicreases activity .Increase in acivity with different bridging group in the following order prophylene >methylene>penthylene> ethylene >butylenes. (Sugimoto Hachiro et al , 1990).

(3)Modification at piperidine moeity-

Activity is depend on location and no of nitrogen atom .Nitrogen atom at 1-position of benzpiperidine is important for activity since N atom at 4-position of benzpiperidine decreases activity .If piperidine ring is replaced with piperazine moeity .then it dicreases activity(Sugimoto Hachiro et al, 2008).

4)Modification at benzyl moeity-

3-position substituted benzyl derivative showed greater activity among -2,-3,-4, substituted reioisomers .If benzene ring is substituted with electron withdrawing nitrogen group and electron donating methyl group shows similar activity .Replacement of benzyl group with phenylethyl group and 2-napthyl group decreased activity(.Kawakami Yoshiyuki et al, 2000)( Sugimoto Hachiro et al, 1990).

Lead development of donepezil -

Once lead compound is identified then it is optimized and characterized for different aspects such as QSAR (quantitative structure activity relationship), SAR(structure activity relationship),synthesis method .

Synthesis of donepezil -

If any compound shows optimum activity in above lead optimization processes then that compounds enter in further stage of lead optimization process. For physicochemical properties, pharmacokinetic, pharmacokidynamic study of lead compound highly purified and large amount of drug is required. Therefore synthesis method for lead compound is important. Sugimoto and co-workers discovered method for synthesis of donezepil with an overall yield of 27.4%. This process involves synthesis of α, β substituted ketones(compound 11) from 1-indanone by aldol condensation. This unsaturation product is catalytically reduced by Palladium to compound (13) but this method needs subzero temperature (-78%) and very toxic chemicals, such as n- butyl litium.( Tsuchiya Yutaka, 1992).

Also many other method have been reported, which are too time consuming or not suitable for large scale production. Stephen discovered efficient synthesis method for donepezil and its analogue. This method involves hydrogenation of pyridine analogues ( compound 7) by using platinum oxide [scheme 2, path A] which is very expensive .If platinum oxide replace with less expensive 5% palladium carbon then it synthesizes compound (8) and compound (11).(US patent 6252081). Chandrashekhar R et al developed economical and efficient method for donepezil synthesis (scheme 2, path β). In first step they condensed 5,6 dimethoxy -1-indan - 1-one [ compound 2] with isonicotinaldehyde compound(3) by modification in standard procedure .By this condensation they formed intermediate compound (6) with 95.8% yield. Afterward he carried out hydrogenation of pyridine ring by using palladium carbon then he observed two main impurities compound (9) and compound (10) due to competitive side reaction of carbonyl ring. In this method they not only maintained different reaction conditions like reaction time, hydrogen pressure, and different solvent but also hydrogenated compound (6) in methanol under hydrogen pressure with 90% yield and 98.5% purity. Final step of donepezil involves benzylation of compound (8). In benzylation nature of solvent and quality benzylbromide plays important role in controlling dibenzyl product ( Elati Chandrashekar R et al, 2006).

If acetone, dichloromethane, acetonitril, isopropylether and dichloromethane gives very poor yield.


In conclusion donepezil hydrochloride is the novel and efficacious cholinesterase inhibitor than other acetylchlinesterase inhibitors. Cholinergic hypothesis shown that cholinergic degradation is the main reason for Alzheimer isease. By target validation it is also proved that donepezil bind to the acetyl cholinesterase and inhibits it. By the target validation it is also proved that donepezil inhibits cholinesterase mainly into the cortical and other areas where high concentration of cholinesterase is situated Is Donepezil has strongly proved cholinergic hypothesis and Also shown that cholineterse inhibition is the main target for treatement of alzimer disease than acetylcholine agonists and acetylcholine precursor. After different structure replacement and attachment to the lead compound of donepezil it is also proved that donepezil has good specificity and activity than other analogues .QSAR study of donepezil and its analogues also shown that donepezil is strongly binds to cholinesterase than other indanone derivatives. Sugimoto and their co workers also synthesized different pyridine and indanone derivatives they also got good efficacy of the results .

For donepezil synthesis different methods have been developed all have some disadvantages and problems regarding hydrogenation step. But chandrashekhar elati et al method has overcome this problems by modifying synthesis methods.


I thanks to Dr Kevine Devine, Dr Annie Bligh, Dr Dhaya Perumal for their guidance to study drug discovery technology module and prepare project(Dissitation) on donepezil discovery processes.