Donepezil: an Important Prototype to the Design of New Drug Candidates for Alzheimer’S Disease

Send Orders for Reprints to [email protected] 2 Mini-Reviews in Medicinal Chemistry, 2014, 14, 2-19 Donepezil: An Important Prototype to the Design of New Drug Candidates for Alzheimer’s Disease Maria Cecília Rodrigues Simões1,2, Flávia Pereira Dias Viegas1,2, Marcella Soares Moreira1, Matheus de Freitas Silva1, Mariana Máximo Riquiel1, Patrícia Mattos da Rosa1, Maísa Rosa Castelli1, Marcelo Henrique dos Santos1,3, Marisi Gomes Soares1 and Claudio Viegas Jr1* 1Laboratório de Fitoquímica e Química Medicinal – LFQM, Instituto de Química, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil; 2Programa de Pós-Graduação em Química, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil; 3Faculdade de Farmácia, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil Abstract: Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with a dramatic socio- economic impact. The progress of AD is characterized by a severe loss in memory and cognition, leading to behavioral changing, depression and death. During the last decades, only a few anticholinergic drugs were launched in the market, mainly acetylcholinesterase inhibitors (AChEIs), with indications for the treatment of initial and moderate stages of AD. The search for new AChEIs, capable to overcome the limitations observed for rivastigmine and tacrine, led Sugimoto and co-workers to the discovery of donepezil. Besides its high potency, donepezil also exhibited high selectivity for AChE and a very low toxicity. In this review, we discuss the main structural and pharmacological attributes that have made donepezil the first choice medicine for AD, and a versatile structural model for the design of novel AChEIs, in spite of multipotent and multitarget-directed ligands. Many recent data from literature transdue great efforts worldwide to produce modifications in the donepezil structure that could result in new bioactive chemical entities with innovative structural pattern. Furthermore, multi-potent ligands have also been designed by molecular hybridization, affording rivastigmine-, tacrine- and huperzine-donepezil potent and selective AChEIs. In a more recent strategy, structural features of donepezil have been used as a model to design multitarget-directed ligands, aiming at the discovery of new effective drug candidates that could exhibit concomitant pharmacological activities as dual or multi- enzymatic inhibitors as genuine innovative therapeutic alternatives for the treatment of AD. Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, Donepezil, Molecular hybridization, Neurodegenerative disorders, Rational drug design. Alzheimer’s Disease (AD) is a neurodegenerative disorder of acetylcholine (ACh), accomplished by aggregation and characterized by an insidious onset and a complex chronic accumulation of extracellular -amyloid (A) peptide as senile multi-factorial progress, affecting hippocampus and frontal neuritic plaques, and intracellular formation of neurofibrillary cortex in brain. This devastating pathology manifests its tangles (NFTs), composed by a hyperphosphorylated form of symptoms as a severe loss in memory, language skills decline the microtubule-associated protein tau, oxidative stress, and and other cognitive impairments, with dramatic behavioral neuronal loss [1, 3, 4]. The Ca2+ ion plays an important role changes that progress to depression and, eventually, death. in the cerebral homeostasis, acting as a second messenger in Recent data points that AD is responsible for ca. 50-60% of the brain. The imbalance of Ca2+ is currently considered one all cases of dementia in people over age 65. It is estimated of the main causes of neurodegeneration due to A effects on that more than 4.5 million people have AD in the US and 18 the capacity of membrane cells to regulate their permeability million worldwide [1-3]. and internal concentration of ions Ca2+. The Ca2+-associated The etiology of AD remains unclear, however many neurodegeneration begins when A causes an increase in the pathophysiologic hallmarks of the disease have been ion influx as a result of the activation of the N-Methyl-D- disclosed and are currently well established. They involve a aspartate receptors by the neurotransmitter glutamate [3b]. complex network of interconnected factors such as a rapid Besides cognitive and motor changes, AD patients also onset of cholinergic dysfunction, with remarkable depletion present diverse behavioral alterations as irritability, anxiety, depression, disorientation and restlessness [4]. To date, AD remains incurable and with few available therapeutic *Address correspondence to this author at the Laboratório de Fitoquímica e alternatives to ameliorate cognition and life quality of the Química Medicinal – LFQM, Instituto de Química, Universidade Federal de patient, arousing special attention and efforts in the search Alfenas, 37130-000, Alfenas-MG, Brazil; Tel: +55-35-32991466; E-mails: [email protected]; and [email protected] for new effective drugs. 1875-5607/14 $58.00+.00 © 2014 Bentham Science Publishers Donepezil: An Important Prototype to the Design of New Drug Candidates Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 1 3 CURRENT AVAILABLE TREATMENT FOR AD plays an important role in the process of amyloid aggregation, and thus could be another target for AChE inhibitors that All current drugs available for the treatment of AD are specifically bind to this site or could act as multi-point only symptomatic, acting mainly as acetylcholinesterase ligands, leading to a subside in the senile plaque formation inhibitors (AChEIs) [3b]. Drugs from this therapeutic class [2]. are supported by the “Cholinergic Hypothesis” that points to restore the cholinergic deficit in central nervous system (CNS) THE DISCOVERY OF DONEPEZIL by selective inhibition of AChE enzyme, and thus result in a The search for a new AChE inhibitor capable to delay of the cognitive decline and in the control of AD overcome rivastigmine limitations in oral availability and symptoms [1, 2, 3]. other pharmacokinetic parameters (e.g. short duration) and During the last two decades, only few anticholinergic hepatotoxic effects of tacrine, led Sugimoto and co-workers drugs have been launched in the market, and are mainly from Eisai Co. to start in 1983 a broad research project indicated for the treatment of mild and moderate stages of involving tacrine derivatives. However, they initially failed the disease, such as tacrine (1), donepezil (2), rivastigmine to develop a new non-toxic and effective tacrine derivative (3) and galanthamine (4, Fig. 1). Another drug recently and turned their attention to a N-benzylpiperazine derivative, approved by FDA is memantine (5, Fig. 1), that acts as an that was originally synthesized and tested for arterial antagonist of glutamate receptors, being indicated for the sclerosis. This compound was tested for AChE inhibition treatment of moderate and severe stages of AD [1, 2, 5]. and showed a very poor activity (IC50 = 12600 nM), but its However, due to a number of adverse peripheral effects arising singular structural feature was intrigating and promising. from the excessive activation of cholinergic system, including Using this compound as a model, they synthesized more than confusion, hallucinations, behavioral abnormalities, nausea, 700 derivatives, to discover that replacing N-benzylpiperazine gastric irritation and hepatotoxicity, these drugs have a quite with N-benzylpiperidine moiety, a dramatic increase in limited clinical use [3b]. Besides the treatment with AChEIs potency for AChE inhibition was observed. In order to develop and memantine, many other therapeutic approaches, such new derivatives with better pharmacological profile for as the use of neurotrophic and anti-inflammatory drugs, clinical tests, they worked in structural optimization of antioxidant compounds and formulations, compounds that N-benzylpiperidine derivatives, and discovered compound could interfere in A-aggregation process have been exploited 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (6, Fig. 2) in the search for new effective therapeutic alternatives. In that showed an IC50 = 560 nM in AChE inhibition [6a, b]. As this context, the more recent approach that has emerged to a new strategy in drug design, they decided to explore the support the design of more effective chemical entities have replacement of an amide group in 6 by a ketone moiety, but considered the multifactorial and complex interconnected with no improvement in activity. Furthermore, the replacement and, in some cases parallel or simultaneous, biochemical of the aliphatic amide (6) with cyclic amide subunit led pathways in AD. This strategy is called Multi-target directed to derivative 7. In a preliminary evaluation, compound ligands (MTDLs) or multifunctional ligands, that is based on 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (7) was identified the fact that using a one-target-direct drug, it is not always as the most potent of the series (IC50 = 98 nM), and was likely that the therapeutical effect will be effective to block selected as a new prototype for further structure-activity disease evolution [3b]. studies, including variation in many other structural subunits and also structurally constrained derivatives. A comparative Considering that AChE enzyme presents two main analysis of pharmacological data revealed that 2-indolinone binding sites for drug interaction, the catalytic site and the subunit of compound 7 could be replaced

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