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BACE-1 and -Secretase As Therapeutic Targets for Alzheimer's Disease

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BACE-1 and -Secretase As Therapeutic Targets for Alzheimer's Disease pharmaceuticals Review BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease Miguel A. Maia 1 and Emília Sousa 1,2,* 1 Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; [email protected] 2 Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal * Correspondence: [email protected]; Tel.: +351-220428689 Received: 15 February 2019; Accepted: 15 March 2019; Published: 19 March 2019 Abstract: Alzheimer’s disease (AD) is a growing global health concern with a massive impact on affected individuals and society. Despite the considerable advances achieved in the understanding of AD pathogenesis, researchers have not been successful in fully identifying the mechanisms involved in disease progression. The amyloid hypothesis, currently the prevalent theory for AD, defends the deposition of β-amyloid protein (Aβ) aggregates as the trigger of a series of events leading to neuronal dysfunction and dementia. Hence, several research and development (R&D) programs have been led by the pharmaceutical industry in an effort to discover effective and safety anti-amyloid agents as disease modifying agents for AD. Among 19 drug candidates identified in the AD pipeline, nine have their mechanism of action centered in the activity of β or γ-secretase proteases, covering almost 50% of the identified agents. These drug candidates must fulfill the general rigid prerequisites for a drug aimed for central nervous system (CNS) penetration and selectivity toward different aspartyl proteases. This review presents the classes of γ-secretase and beta-site APP cleaving enzyme 1 (BACE-1) inhibitors under development, highlighting their structure-activity relationship, among other physical-chemistry aspects important for the successful development of new anti-AD pharmacological agents. Keywords: Alzheimer’s disease; amyloid hypothesis; γ-secretase; BACE-1 1. Introduction 1.1. Alzheimer’s Disease–Epidemiology AD is recognized by the World Health Organization (WHO) as a global public health priority [1]. Notwithstanding the advances in the understanding of AD pathogenesis since Alois Alzheimer reported the first case in 1907 [2], there are still a lot of uncertainties regarding the mechanisms involved in disease progression. AD is the most prevalent cause of dementia-acquired progressive cognitive impairment sufficient to impact on activities of daily living, being a major cause of dependence, disability and mortality. The WHO estimated that in 2010, 35.6 million worldwide were living with dementia [3]. This figure is projected to almost double every 20 years, reaching 65.7 million by 2030 and 115.4 million by 2050. Europe, with an estimated 10 million cases of dementia in 2010 and acquiring progressively an old population structure [4], has a projected increase to 14 million cases in 2030 [1]. In the United States of America (USA), the total annual payments for health care, long-term care and hospice care for people with AD or other dementias are projected to increase from $259 billion in 2017 to more than $1.1 trillion in 2050 [5]. These numbers show the dramatic impact that AD and the other dementias will have in the health care systems in the future. Pharmaceuticals 2019, 12, 41; doi:10.3390/ph12010041 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2018,, 11,, 2 of 31 Pharmaceuticals 2018, 11, 2 of 31 in 2017 to more than $1.1 trillion in 2050 [5]. These numbers show the dramatic impact that AD and inin 20172017 toto moremore thanthan $1.1$1.1 trilliontrillion inin 20502050 [5].[5]. ThesThese numbers show the dramatic impact that AD and the other dementias will have in the health care systems in the future. the otherPharmaceuticals dementias2019 will, 12 have, 41 in the health care systems in the future. 2 of 31 1.2. Pathology 1.2. Pathology1.2. Pathology The main characteristics of Alzheimer’s pathology are the presence of amyloid plaques and The main characteristics of Alzheimer’s pathology are the presence of amyloid plaques and neurofibrillaryThe tangles main characteristics (aggregates of of hyperphosphorylated Alzheimer’s pathology tau are protein) the presence [5]. In addition, of amyloid neuropil plaques and neurofibrillary tangles (aggregates of hyperphosphorylated tau protein) [5].. In addition, neuropil treads,neurofibrillary dystrophic neurites, tangles associated (aggregates astrogliosis, of hyperphosphorylated and microglial activation tau protein) frequently [5]. In addition,coexist. The neuropil treads, dystrophic neurites, associated astrogliosis, and microglial activation frequently coexist. The downstreamtreads, consequences dystrophic neurites, of these pathological associated astrogliosis, processes include and microglial neurodegeneration activation with frequently synaptic coexist. downstream consequences of these pathological processes include neurodegeneration with synaptic and neuronalThe downstream loss leading consequences to macroscopic of these atrophy pathological [6]. Research processes suggests include that neurodegenerationthe brain changes with and neuronal loss leading to macroscopic atrophy [6]. Research suggests that the brain changes associatedsynaptic with andAD neuronalmay begin loss 20 leadingor more to years macroscopic before symptoms atrophy [ 6appear]. Research [7,8]. suggestsWhen the that initial the brain associated with AD may begin 20 or more years before symptoms appear [7,8]. When the initial changeschanges occur, associatedthe brain withcompensates AD may beginfor them, 20 or enabling more years individuals before symptoms to continue appear to [7function,8]. When the changes occur, the brain compensates for them, enabling individuals to continue to function normally.initial As changesneuronal occur, damage the brainincreases, compensates the brain forcan them, no longer enabling compensate individuals for tothe continue changes toand function normally. As neuronal damage increases, the brain can no longer compensate for the changes and individualsnormally. show As subtle neuronal cognitive damage decline. increases, Later, theneuronal brain candamage no longer is so significant compensate that for individuals the changes and individualsindividuals showshow subtlesubtle cognitivecognitive decline.decline. Later,Later, neneuronal damage is so significant that individuals show obviousindividuals cognitive show decline, subtle cognitive including decline. symptoms Later, such neuronal as memory damage loss isor so confusion significant as thatto time individuals or show obvious cognitive decline, including symptoms such as memory loss or confusion as to time or place [5].show obvious cognitive decline, including symptoms such as memory loss or confusion as to time or place [5].place [5]. 1.3. Current Pharmacology and Drug Development 1.3. Current1.3. Current Pharmacology Pharmacology and Drug and Development Drug Development Currently, five drugs are approved for the treatment of AD (Table 1). These include four Currently,Currently, five drugs five drugsare approved are approved for the for treatment the treatment of AD of (Table AD (Table 1). These1). These include include four four acetylcholinesterase inhibitors (AChEi) - tacrine (approved in 1993), donepezil (approved in 1996), acetylcholinesteraseacetylcholinesterase inhibitors inhibitors (AChEi) (AChEi) - tacrine - tacrine(approved (approved in 1993), in donepezil 1993), donepezil (approved (approved in 1996), in 1996), rivastigmine (1998), and galantamine (approved in 2001) [9]. This class of drugs act by blocking the rivastigminerivastigmine (1998), (1998),and galantamin and galantaminee (approved (approved in 2001) in[9]. 2001) This [cl9].ass This of drugs class act of drugsby blocking act by the blocking process that downregulate the neurotransmitter acetylcholine (ACh), a key signaling agent for nerve processthe that process downregulate that downregulate the neurotransmitter the neurotransmitter acetylcholine acetylcholine (ACh), a key (ACh), signaling a key agent signaling for nerve agent for cells communication. Although tacrine has been the first AChEi approved by Food and Drug cells communication.nerve cells communication. Although tacrine Although has tacrinebeen the has first been AChEi the first approved AChEi approved by Food by and Food Drug and Drug Administration (FDA), it is currently not used due to its hepatotoxicity [10]. Donepezil, rivastigmine, AdministrationAdministration (FDA), (FDA), it is currently it is currently not used not due used to dueits hepatotoxicity to its hepatotoxicity [10]. Donepezil, [10]. Donepezil, rivastigmine, rivastigmine, and galantamine belong to the same therapeutic class, but present different pharmacodynamic (PD) and galantamineand galantamine belong belongto the same to the therapeutic same therapeutic class, but class, present but present different different pharmacodynamic pharmacodynamic (PD) (PD) and pharmacokinetic (PK) profiles: donepezil is a noncompetitive reversible AChEi; galantamine is and pharmacokineticand pharmacokinetic (PK) profiles: (PK) profiles: donepezil donepezil is a noncompetitive is a noncompetitive reversible reversible AChEi; AChEi; galantamine galantamine is is a selective reversible AChEi and a positive allosteric modulator of nicotinic ACh receptors; and a selectivea selective reversible reversible AChEi
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