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Med Res Rev. 2019;1-46. wileyonlinelibrary.com/journal/med © 2019 Wiley Periodicals, Inc.
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1
Received: 18 February 2019
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Revised: 22 May 2019
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Accepted: 13 June 2019
DOI: 10.1002/med.21622
REVIEW ARTICLE
BACE1 inhibitors: Current status and future
directions in treating Alzheimer's disease
Nour M. Moussa‐Pacha
1
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Shifaa M. Abdin
1
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Hany A. Omar
1,2,3
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Hasan Alniss
1,2
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Taleb H. Al‐Tel
1,2
1
Sharjah Institute for Medical Research,
University of Sharjah, Sharjah, United Arab
Emirates
2
College of Pharmacy and College of
Medicine, University of Sharjah, Sharjah,
United Arab Emirates
3
Faculty of Pharmacy, Beni‐Suef University,
Beni‐Suef, Egypt
Correspondence
Taleb H. Al‐Tel, Sharjah Institute for Medical
Research, University of Sharjah, P.O. Box
27272 Sharjah, UAE.
Email: taltal@sharjah.ac.ae
Funding information
University of Sharjah, Grant/Award Number:
15011101007 and 15011101002
Abstract
Alzheimer's disease (AD) is an irreversible, progressive
neurodegenerative brain disorder with no current cure.
One of the important therapeutic approaches of AD is the
inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is
involved in the rate‐limiting step of the cleavage process
of the amyloid precursor protein (APP) leading to the
generation of the neurotoxic amyloid β(Aβ) protein after
the γ‐secretase completes its function. The produced
insoluble Aβaggregates lead to plaques deposition and
neurodegeneration. BACE1 is, therefore, one of the
attractive targets for the treatment of AD. This approach
led to the development of potent BACE1 inhibitors, many of
Abbreviations: AChE, Acetylcholinesterase; AD, Alzheimer's disease; AD3, Alzheimer's disease gene 3; AD4, Alzheimer's disease gene 4; Ala, Alanine
amino acid; ALS, Amyotrophic lateral sclerosis; APH‐1, Anterior pharynx‐defective 1; APOE, Apolipoprotein E; APP, Amyloid precursor protein; APPsα,
Soluble amyloid precursor protein α‐fragment; APPsβ, Soluble amyloid precursor protein β‐fragment; Arg, Arginine amino acid; ARIA, Amyloid‐related
imaging abnormalities; ARIA‐E, Amyloid‐related imaging abnormalities attributed to edema or effusion; Asn, Aspargine amino acid; Asp, Aspartic acid;
ATP, Adenosine tri‐phosphate; Aβ, Amyloid βprotein; Aβ40, Amyloid βprotein with 40 amino acids; Aβ42, Amyloid βprotein with 42 amino acids; Aβo,
Soluble Aβoligomer; BACE1, Beta‐site amyloid precursor protein cleaving enzyme‐1; BACE2, Beta‐site amyloid precursor protein cleaving enzyme‐2;
BBB, Blood‐brain barrier; CatD, Cathepsin D; CatE, Cathepsin E; CB1, Cannabinoid type 1 receptor; CB2, Cannabinoid type 2 receptor; cHEA, Cyclic
hydroxyethylamine; CML, Chronic myeloid leukemia; CNS, Central nervous system; CSF, Cerebrospinal fluid; Cys199, Cysteine 199 amino acid; DMF, 5,7‐
Dimethoxyflavone; ECS, Endocannabinoid system; FDA, Food and Drug Administration; FRET, Fluorescence resonance energy transfer; Glu, Glutamic
acid; Gln, Glutamine amino acid; Gly, Glycine amino acid; GSK‐3, Glycogen synthase kinase‐3; GSK‐3β, Glycogen synthase kinase‐3β; HEA,
Hydroxyethylamine; HIV, Human immunodeficiency Virus; HTS, High throughput screening; IC50, 50% Inhibitory concentration; Ig, Immunoglobulin; Ile,
Isoleucine amino acid; Ki, Inhibitory constant; KP, Kaempferia parviflora;LC‐MS/MS., Liquid chromatography mass spectrometry; Leu, Leucine amino acid;
mAbs, Monoclonal antibodies; MRI, Magnetic resonance imaging; MTLs, Multitarget ligands; MTDLs, Multitarget‐directed ligands; MWM, Morris water
maze; Nct, Nicastrin; NFT, Neurofibrillary tangles; NMDA, N‐methyl D‐aspartate; NRG1, Neuregulin‐1; P‐gp, P‐glycoprotein; P‐tau, Phosphorylated tau;
PEN‐2, Presenilin enhancer 2; PK, Pharmacokinetics; PMF, 3,5,7,3′,4′‐Pentamethoxyflavone; PrPC, Cellular prion protein; PS1, Presenillin 1; PS2,
Presenillin 2; RIPK1, Receptor‐interacting serine/threonine‐protein kinase 1; SAR, Structure activity relationship; Ser, Serine amino acid; SEZ6, Seizure
protein 6; SFKs, Src family of nonreceptor tyrosine kinases; SOD1, Superoxide dismutase 1; SRC, Sarcoma‐family kinases; SRIS, Systemic inflammatory
response syndrome; TGN, Trans‐Golgi network; THC, Tetrahydrocannabinol; Thr, Threonine amino acid; TMF, 5,7,4′‐Trimethoxyflavone; Trp, Tryptophan
amino acid; Tyr, Tyrosine amino acid; Val, Valine amino acid.
Nour M. Moussa‐Pacha and Shifaa M. Abdin contributed equally to this study.
which were advanced to late stages in clinical trials.
Nonetheless, the high failure rate of lead drug candidates
targeting BACE1 brought to the forefront the need for
finding new targets to uncover the mystery behind AD. In
this review, we aim to discuss the most promising classes of
BACE1 inhibitors with a description and analysis of their
pharmacodynamic and pharmacokinetic parameters, with
more focus on the lead drug candidates that reached late
stages of clinical trials, such as MK8931, AZD‐3293,
JNJ‐54861911, E2609, and CNP520. In addition, the
manuscript discusses the safety concerns and insignificant
physiological effects, which were highlighted for the most
successful BACE1 inhibitors. Furthermore, the review
demonstrates with increasing evidence that despite
tremendous efforts and promising results conceived with
BACE1 inhibitors, the latest studies suggest that their
clinical use for treating Alzheimer's disease should be
reconsidered. Finally, the review sheds light on alternative
therapeutic options for targeting AD.
KEYWORDS
Alzheimer's disease, amyloid hypothesis, amyloid‐β, BACE‐1
inhibitors, Fyn, GSK‐3β,β‐secretase
1
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INTRODUCTION
Dementia is a syndrome that encompasses a variety of symptoms with gradual progression, which hinders early
diagnosis of the disease. Despite the progressive development of the symptoms, not all individuals share the
same rate of disease progression. Dementia can be exhibited as a manifestation of multiple diseases. However,
the dominant form of dementia is known to be Alzheimer's disease (AD).
1
AD is a progressive neurodegenerative
disease characterized by memory and neuronal loss, difficulties in speaking, problem‐solving, and other cognitive
skills, along with changes in the mood and behavior, which interfere with the person's daily performance.
2,3
These
symptoms result from the neuronal cell damage that is responsible for the cognitive function in the brain. This
damage may extend to neurons in different parts of the brain. Thus, additional adverse symptoms may appear on
the affected individual. Living with this disease can be very disabling, especially, that AD could be ultimately fatal. It
is believed that Alzheimer's is a complex disease where several factors contribute to its development. The
uttermost risk factors and causes for AD include age, lifestyle, environmental factors, family history, and bearing
the Apolipoprotein E (APOE)‐ε4 gene.
4
Moreover, genetic mutations are one of the causative factors of AD, as AD
genes were reported to be expressed on different chromosomes causing subsequent mutation in the expressed
gene product.
2
For instance, AD gene 3 (AD3) was found to be located on chromosome 14 leading to mutations on
Presenilin 1 gene. In parallel, AD gene 4 (AD4) is considered as a candidate for chromosome 1, which would cause a
mutation of Presenilin 2 gene.
2
In addition, one of the identified genetic mutations associated with AD is the
presence of AD gene 1 on chromosome 21 causing abnormal changes in the amyloid precursor protein (APP).
2
2
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MOUSSA‐PACHA ET AL.
These genetic changes are affecting the function of vital gene products in the brain leading ultimately to the
abnormality of AD, specifically familial AD, which is characterized as an early onset form of AD.
2
It is worth mentioning that dementia is considered the 6th leading cause of death in the United States.
5
In 2015,
around 47.47 million people worldwide were diagnosed with dementia, and the number of people living with
dementia increases with the population ages.
6
It is expected to have these numbers triple from 50 million to
152 million by 2050.
6
Moreover, AD interferes with numerous aspects of human life including social, economic,
physical, and psychological aspects, which create a tremendous economic burden. Hence, the global socioeconomic
cost of dementia in 2015 was around US$ 818 billion.
6
The fact that such a life‐threatening disease was not yet
battled with potent disease‐modifying drugs made AD on the top agenda of many researchers and scientists, with
the hope to win the battle of AD treatment. Currently, there are several ongoing clinical trials for potential new
medications for AD (Table 1). However, the latest news from many of these clinical trials indicated a high failure
rate of many lead drug candidates, specifically the ones targeting β‐site APP cleaving enzyme 1 (BACE1).
7-9
Moreover, the elegant contributions from Cummings et al highlighted several small molecules BACE1 inhibitors
that are currently in clinical trials for AD treatment. Around 26 candidates were introduced in clinical trials,
including agents that target the amyloid‐β(Aβ) protein through BACE1 inhibition and others as immunotherapies.
10
In this article, we report the latest research results on AD, by covering the most recent molecules developed across
multiple classes of BACE1 inhibitors and focusing on the fate of the developed BACE1 inhibitors that advanced into
clinical trials. In addition, the latest developments in the field that aim to provide promising disease‐modifying
TABLE 1 BACE1 Inhibitors in different stages of clinical trials
Compd. name/code and structure Class Phase NCT number Status Sponsor Ref.
Anti‐
amyloid,
BACE1
inhibitor
Phase II/
III
clinical
trials
NCT02245737 Ongoing AstraZeneca, Eli
Lilly & Co.
7,8
Anti‐
amyloid,
BACE
inhibitor
Phase III
clinical
trials
NCT01739348 Terminated Merck
7,8
Anti‐
amyloid,
BACE
inhibitor
Phase III
clinical
trials
NCT03036280 Ongoing Eisai, Biogen
7,8
Anti‐
amyloid,
BACE
inhibitor
Phase II/
III
clinical
trials
NCT02406027 Terminated Janssen
7,8
CNP520 BACE1
inhibitor
Phase II/
III
clinical
trials
NCT02576639 Ongoing Novartis, Amgen
9
Abbreviation: BACE1, β‐site APP cleaving enzyme 1.
MOUSSA‐PACHA ET AL.
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3
drugs, such as immunotherapies and targeting routes other than the amyloid cascade hypothesis, are also
discussed.
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ALZHEIMER'S DISEASE PATHOLOGY AND TARGETS
The main neuropathic hallmarks of AD are characterized as two lesions in the brain, namely, the extracellular
amyloid plaques and the intracellular neurofibrillary tangles (NFT) (Figure 1).
11
They appear initially in the
hippocampus that is responsible for the consolidation of information flow from short‐memory to long‐memory and
extend to the cortical gray matter killing cells in the brain and compromising their functions.
12
Neurofibrillary tangles are insoluble bundles of fibers, comprised of the intracellular aggregation of
hyperphosphorylated tau (p‐tau) protein, which is responsible for microtubules stabilization. The presence of
these tangles is not limited to AD disease as they can also be found in other neurodegenerative disorders like Kuf's
disease and subacute sclerosing panencephalitis.
3
On the other hand, the neuritic plaques, or senile plaques, are
considered as a characteristic presenilin feature of AD, and they are visualized as spherical lesions surrounded by
an array of abnormal dendrites and axons, which results from the extracellular aggregation of amyloid‐β(Aβ)
protein following the sequential cleavage of APP.
2
In the early steps of the disease pathogenesis, the accumulation
of Aβproteins is of significant concern as it leads to the formation of NFT, and has a neurotoxic and
neuroinflammatory effects that result in synaptic loss and neuronal cell death.
13
APP is a large type 1 membrane
protein present in many tissues throughout the body and it is mainly expressed in the brain and the kidneys.
13
There are three enzymes involved in the processing of this protein as illustrated in Figure 2, α‐,β‐, and
γ‐secretases.
14,15
The cleavage of APP by each of these three enzymes result in different end products. One of
these end products, which is the insoluble Aβprotein, is considered the leading cause of AD abnormality (Figure
2).
16
Despite the fact that AD is significantly correlated to the accumulation of the insoluble Aβplaques,
nonetheless, recent studies reported that the soluble form of amyloid‐β,Aβo oligomers also participate greatly in
these neurodegenerative conditions by acting as neurotoxin causing severe synaptic damage.
17,18
In addition, it was
FIGURE 1 Pathological difference between neurons of the healthy brain and AD patient's brain. Amyloid
plaque accumulation is a key feature of AD. Amyloid plaque has been detected between the neurons in AD brain,
along with the formation of abnormal neurofibrillary tangles within the neuronal cells. Both lesions have a toxic and
degenerative effect on the neurons, and overall brain atrophy is observed. AD, Alzheimer's disease [Color figure
can be viewed at wileyonlinelibrary.com]
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MOUSSA‐PACHA ET AL.
reported that these oligomers can induce their neurotoxic response by glial cells involvement.
18
In vivo studies to
further explore the cytotoxic effect of Aβoligomers were conducted. In one study, Aβoligomers were injected to
rats hippocampus, which resulted in several neurological defects such as loss of synaptic transmission, a decline in
cognitive function along with cell death upon the aggregation of Aβoligomers.
19
In fact, numerous reports confirm the toxic role of Aβoligomers in AD pathology, where they emphasize on the
fact that a true distinction should be made on whether Aβplaques or the soluble oligomers are the true targets to
peruse for alleviating AD hallmarks.
20
This finding was enforced from the results of a study comparing the effects of
fibrillar vs oligomeric forms of Aβ. The results of this study indicated that rats injected with Aβoligomers exhibited
severe neurological deficits with greater neurodegeneration and inflammation compared with rats injected with a
fibrillar form of Aβ.
21
Further evidence on the harmful role of Aβoligomers has emerged from the need to design
therapeutic strategies that eradicate Aβoligomers before the progression and development of Aβplaques, else the
therapy would not yield beneficial outcome.
22
Henceforth, it is evident that the accumulation of Aβoligomers plays
a vital role in AD progression, where AD severity could be linked to the degree of Aβaccumulation, which can
manifest its neurotoxic effect by a wide variety of mechanisms including apoptosis promotion, synaptic loss, pore
formation, and loss of membrane potential.
23
Other findings indicated that, when the substrate APP, is bound to α‐secretase in the nonamyloidogenic
pathway, it produces an ectodomain, which is a soluble amyloid precursor protein α‐fragment (APPsα)leaving
behind C‐terminus fragment bound to the membrane (C83), which will be converted by γ‐secretase to a
protein fragment called P3.
15
Henceforth, the enzymatic action of α‐secretase is not leading to the formation
and accumulation of the insoluble Aβprotein, which rules out the need for considering this pathway as an
FIGURE 2 APP metabolism by secretase enzymes. APP is a large type 1 membrane protein that is subjected to
three enzymes, α‐β‐, and γ‐secretases, which generate different end products. When α‐secretase competes with
β‐secretase for the APP substrate, a soluble ectodomain called APPsαis produced leaving behind a C‐terminus
fragment bound to the membrane (C83) that will be processed to a protein fragment called P3 by the effect of
γ‐secretase. Accordingly, α‐secretase action is not leading to the formation of any insoluble Aβprotein and this
pathway is known as the nonamyloidogenic pathway. On the other side, the amyloidogenic pathway starts from the
cleavage at the N‐terminus of APP by β‐secretase (BACE1), which leads to the production of two fragments, the
soluble ectodomain APPsβand the membrane‐bound C‐terminus (C99). C99 is then processed by γ‐secretase and
generate two types of Aβproteins, Aβ40 and Aβ42. Aβ42 is a key player in AD pathogenesis. AD, Alzheimer's
disease; APP, amyloid precursor protein [Color figure can be viewed at wileyonlinelibrary.com]
MOUSSA‐PACHA ET AL.
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option to target of AD. On the contrary, it was found that the biosynthesis of Aβstarts with the cleavage at
the N‐terminus of the protein by β‐site APP cleaving enzyme 1 (BACE1). This leads to the production of two
fragments, the ectodomain that is a soluble amyloid precursor protein β‐fragment (APPsβ)andthe
membrane‐bound C‐terminus (C99). C99 is then processed by γ‐secretase complex which is constituted of
four transmembrane proteins: presenilin (PS1 or PS2), nicastrin (Nct), anterior pharynx‐defective
phenotype (APH‐1), and presenilin enhancer 2 (PEN‐2).
15
The interaction of C99 with γ‐secretase leads to
the production of two types of Aβproteins, Aβ40 and Aβ42.
24
Aβ42 is a critical player in AD pathogenesis
according to the latest evidence, which has entitled this etiology as the “amyloid cascade hypothesis.”
25
Interestingly, apart from the amyloid hypothesis, there are several Aβindependent phenomena's that can
induce and contribute to AD severe hallmarks. For instance, it was reported that the accumulation
of C99 could foster great neurological deficits, as it wasobservedinaninvivotransgenicmicemodelwhere
C99 accumulation was induced without Aβdisposition or tau phosphorylation. These mice exhibited an early
apathy like behavior and synaptic plasticity alteration, which can be traced to be solely dependent
on C99 accumulation apart from any abnormal Aβaccumulation.
26
In addition, the Lauritzen group,
27
revealed that C99 accumulation can be directly associated with endosomal‐autophagic‐lysosomal
dysfunction, which is one of the famous features of AD. In this report, it was demonstrated that in two in
vivo transgenic mice models that have an accumulation of C99, indicated that this fragment is the main driver
of endosomal‐autophagic‐lysosomal dysfunction.
27
Moreover, Lauritzen et al,
28
discovered important
amount of evidence to support the role of C99 accumulation and oligomerization with early neurotoxicity
and onset of AD, as these reports elucidate that this fragment can mediate its toxicity by causing lysosomal
autophagic dysfunction, brain alteration, and memory‐related behavioral changes.
28
Additional important
findings reported by the Nixon group,
29
indicated that the endosomal‐autophagic lysosomal dysfunction
induced by C99 accumulation could be one of the key drivers to AD abnormality. In fact, it was reported that
thereisacloseassociationbetweenβ‐amyloidogenesis and endosomal‐autophagic lysosomal dysfunction,
where both pathological aspects stem from the common genetic basis and cooperate to produce the
multiple features of AD.
29
Together these reports indicated the complexity of AD pathology and
confirmed the toxic effect of C99, which could underlie some of the early‐stage anatomical hallmarks of
Alzheimer's disease etiology.
Studies suggested that Aβ42 aggregates are responsible for the formation of senile plaques, which is believed to
initiate a neurotoxic cascade that will end up with the clinical manifestations of Alzheimer's disease.
30
Thus, targeting AD
might be achieved by inhibiting the Aβproduction, promoting its clearance, inhibiting its aggregation, or restricting the
toxic effects of the abnormal accumulation of Aβdeposits. These suggested approaches are considered attractive anti‐
amyloid strategies for tackling AD (Figure 3).
30,31
However, blocking the formation of the aggregates is generally believed
to be technically challenging to achieve. Moreover, the mechanism of Aβclearance has not been fully understood yet, and
up to date, there is no viable tactic to promote Aβclearance. These challenges have therefore pushed the research wheel
over the past 9 years to focus mainly on blocking the Aβgeneration. This goal can be attained by blocking the enzymes
involved in the production of Aβ‐protein. Thus, the aim of slowing the AD progression can result from blocking Aβ
generation when targeting both β‐and γ‐secretases.
31
Inhibition of γ‐secretase aimed to knock out the two most important proteins (PS1 and PS2) in the γ‐secretase
complex, which are the integral membrane proteins found in the endoplasmic reticulum and Golgi apparatus. These
proteins control the Notch signaling pathway which is accountable for cell differentiation and proliferation during
embryonic development.
32
Despite the fact that it was very appealing for many researchers to develop several
inhibitors for γ‐secretase, the results of its inhibition were not satisfactory. Transgenic PS1 knockout mice were
unhealthy, not fertile and had lagging subventricular areas and cortical dysplasia.
32
Thus, blocking γ‐secretase is more likely to result in adverse effects due to the vital biological function of PS1.
The undesirable results obtained from γ‐secretase inhibition drove the attention toward the inhibition of
β‐Secretase as an attractive target to reverse or stop the disease progression.
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MOUSSA‐PACHA ET AL.
β‐secretase is an aspartyl protease that cleaves the APP in the lumina and is believed to be the rate‐determining
step in the Aβgeneration. BACE1 inhibition provides multiple advantages, among which is the prevention of Aβ
formation at an early stage of APP processing. Moreover, BACE1 knockout homozygote mice exhibited a total loss
of Aβproduction without any significant side effect.
32
Moreover, many in vivo studies confirmed that β‐secretase
play a vital role in AD progression and the use of BACE1 inhibitors improved the neurological function and
surpassed the neurological defects imposed in mice of AD model.
33
For example, in a recent study utilizing NB‐360
as BACE1 inhibitor in mice with familial Alzheimer disease, the administration of this agent resulted in the
enhancement of neuronal activity and the improvement of memory.
34
These effects were attributed to the ability
of NB‐360 to reduce the formation of Aβoligomers. When researchers reintroduced soluble Aβoligomers to these
mice, the positive implication of NB‐360 was reverted and the mice showed again the typical symptoms of AD.
34
Therefore, these in vivo studies revealed evidence on the implication of BACE1 inhibitors as a valid approach to
tackle AD and that Aβoligomers are having a downstream effect on AD progression.
35
Based on many reports, even BACE1 inhibitors have the ability to reduce the production and to lower the levels
of Aβ, it is still not clear if these effects would translate into a “treatment”of AD disease. These results are
connected to the failure of many BACE1 inhibitors in clinical trials which reflects on the controversy between the
highly effective BACE1 inhibition‐mediated treatments of AD in animal models vs the failure in clinical trials.
FIGURE 3 Amyloid cascade hypothesis and therapeutic approaches. Since Aβ42 aggregates are believed to be
the key player in the formation of senile plaques that will initiate a neurotoxic cascade resulting in the appearance
of AD clinical manifestations, targeting AD may be attained by inhibiting the Aβproduction, inhibiting its
aggregation, promoting its clearance, or restricting the toxic effects of the abnormal accumulation of Aβdeposits.
All of these suggested approaches are considered attractive antiamyloid strategies for tackling AD. However,
researchers have faced several challenges in most of these approaches, pushing the research wheel mainly on
blocking the Aβgeneration by blocking the enzymes involved in the production of Aβ‐protein, both β‐and
γ‐secretases. AD, Alzheimer's disease [Color figure can be viewed at wileyonlinelibrary.com]
MOUSSA‐PACHA ET AL.
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One possible explanation for such an incongruity might be related to the difference in the genetic background
between mice and humans. Such a genetic difference between the two species was fruitfully discussed before.
36,37
However, the persistent negative results of BACE1 inhibitors in clinical trials should not be overlooked since these
results contain important lessons to the future. While some understood these findings as a judgment of amyloid
cascade hypothesis (ACH) validity, however, such a conclusion appears to be premature; since the ACH remains the
most recognized theory when compared with other alternative interpretations of AD pathology. At this junction,
the dark picture of clinical trials results using BACE1 inhibitors and perhaps other Aβ‐targeted therapies does not
indicate that such treatments will be in place in the near future. Furthermore, due to the complexity of AD, BACE1
inhibition alone is insufficient for clinical improvement via the reduction of Aβ. This approach may have
to be combined with other strategies like Aβand/or tau clearance for disease‐modifying effects. In summary, with
these unsuccessful clinical trials in hand, many lessons to the future can be framed as follows: (a) familial
Alzheimer's disease (FAD) and sporadic Alzheimer's disease (SAD) should be contemplated as two markedly
different diseases as far as the mechanisms of amyloid production are concerned. (b) Human trials of BACE1
inhibitors should be conducted separately, with two independent familial AD and sporadic AD cohorts. (c) Targeting
other aspects of Alzheimer's disease other than β‐secretase of the Aβprecursor protein might have comparable
impacts in familial and sporadic AD lesions.
Another potential method to target AD is the inhibition of tau aggregation by small molecules to avoid
the development of tau lesions, however, unfortunately, this approach lacks a complete understanding of the
pathology of tau.
38
Taken together these findings paved the way for the design and synthesis of BACE1 inhibitors and in the
following sections, the most promising motifs are discussed.
3
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BACE1 AS A POTENTIAL TARGET FOR THE TREATMENT OF
ALZHEIMER'S DISEASE
3.1
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Structure and properties of BACE1
BACE1 has taken a central stage in targeting AD and several companies have developed BACE1 inhibitors to tackle
this devastating illness and many of these inhibitors reached advanced stages in clinical trials. Inhibition of BACE1
is therefore considered one of the major methodologies to address AD.
13
However, many obstacles need to be overcome to design effective and physiologically significant BACE1
inhibitor with minimal off‐target effects. BACE1 is a structurally challenging protein that possesses structural
similarities with other aspartyl proteases,
39
a family that includes many enzymes distributed in different parts of
the human body such as BACE2, pepsin, renin, cathepsin D (CatD), and cathepsin E (CatE). Thus, achieving
selectivity in BACE1 inhibition without affecting other proteases is crucial for developing effective BACE1
inhibitors and eliminating the off‐target side effects.
39,40
Furthermore, an additional challenge in the discovery of BACE1 inhibitor is related to the size of BACE1 active
site, which consists of catalytic aspartic acid residues, flap, and 10S loop, which is known to be of a relatively large
size (Figure 4), therefore, having a small molecule to occupy this large active site represents a grand challenge.
31
In addition, the issue of the ability of these compounds to pass the blood‐brain barrier (BBB), is another
challenge.
41
Furthermore, many of the developed BACE1 inhibitors were prone to efflux by P‐glycoprotein (P‐gp),
which complicates the process of drug entry to the brain, even when brain permeability is attained via BBB
penetration. P‐gp efflux is, therefore another limiting factor of these inhibitors.
41
Despite the above potential hurdles in the design of BACE1 inhibitors, many laboratories succeeded in
developing selective, potent, and bioavailable inhibitors. To date, many of these compounds have shown promising
clinical effects, however, none have passed the final stages of clinical trials yet to receive final FDA approval and
reach the market.
8
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MOUSSA‐PACHA ET AL.
Before starting to delineate the chemistry and structure‐activity relationships (SAR) of BACE1 inhibitors, it is
worth discussing some structural features of the enzyme. BACE1 belongs to type I transmembrane aspartyl
proteases family and consists of 501 amino acids (Figure 5).
42
It has an N‐terminal‐,aC‐terminal‐, and an
inter‐domain, which connects the N‐terminal and C‐terminal domains.
Most of the structural characteristics of BACE1 were exploited in the discovery of the earliest BACE1 inhibitors
OM99‐2, an eight‐residue transition‐state inhibitor, that showed a potent inhibitory activity for BACE1 with
K
i
= 1.6 nM. The interaction of the OM99‐2 eight residues with the BACE1 active site is illustrated in Figure 6.
43,44
Twenty‐eight of the amino acid residues composing the active site of BACE1 were recognized as ligand‐binding
site and all of them within 5 Å from the ligand.
45
The ligand‐binding site is presented as a surface including the
subpockets S1, S2, S3, S4, S1′,S2′,S3′, and S4′.
46
Moreover, optimal BACE1 activity is achieved at acidic pH, as
BACE1 is located within acidic intracellular compartments including trans‐Golgi network (TGN) and endosomes
where it cleaves its substrates leading to the formation of Aβprotein fragments. The optimal enzyme activity under
acidic conditions suggests that a BACE1 inhibitor having a basic amine residue with a pK
a
of ca. 6.0 or more would
exhibit better binding affinity.
41
The catalytic dyad, Asp32, and Asp228 are located in the ligand‐binding sites and
are crucial for the proteolytic activity of the enzyme.
47
Binding of a ligand to these two amino acids enhances its
binding affinity and in turn, its potency.
The β‐secretase active site is shielded by a β‐hairpin loop, which is a large part of the binding site, between
Val67 and Glu77 in the N‐terminal lobe. It is usually known as the “flap”and considered the most flexible part of
the active site that is believed to control the access of the substrate to the active site by its conformational
changes. When the active site is in the inactive form, the flap tends to be in its open conformation. However, the
presence of a substrate or inhibitor stabilizes the flap in its closed form.
47
An important residue in the flap is the Tyr71 that takes a conformation complementary to the nature and shape
of the ligand when bound to the binding site. Changing the flap position relative to the catalytic aspartic acid
residues affords a mean for the substrate or the ligand to diffuse in and out of the active
site. Furthermore, it is also documented that Tyr71 flexibility plays a fundamental role in defining
BACE1 confirmation as opened or closed.
47
The ability of Tyr71 hydroxyl group to form a hydrogen bond with
FIGURE 4 The binding pocket of BACE1 contains three important parts, A, the catalytic aspartic acid residues
that are crucial for the proteolytic activity of BACE1, B, the flap that is the most flexible part of the binding site and
controls the access of the substrate, and C, the 10 seconds loop that is located near the S3 pocket [Color figure can
be viewed at wileyonlinelibrary.com]
MOUSSA‐PACHA ET AL.
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9
the NH of the Trp76 side chain permits the Tyr71 to physically separate the S1 and S2′subpockets, resulting in a
closed BACE1 confirmation. While the open BACE1 conformation is observed when the flap moves away from the
catalytic Asp, which in turn abolishes the formation of a hydrogen bond between the residues Tyr71 and Trp76, in
that case, Tyr71 will not be appropriately positioned between the S1 and S2′subpockets. In other words, the
existence of a hydrogen bond between the residues Tyr71 and Trp76 implies that the conformation of BACE1 as
closed, and the absence of this H‐bond describe it as open.
47,48
Molecular dynamics simulation studies proved that
the open and closed forms are freely accessible at room temperature, which implicates the conformational
flexibility of Tyr71 and the active site flap in BACE1. This unique structure and composition of this enzyme have
permitted the design of a variety of inhibitors.
41
FIGURE 5 Structural characteristics of BACE1 binding site. BACE1 is a type I transmembrane aspartyl protease
consists of 501 different amino acids with a N‐terminal‐,aC‐terminal‐, and an interdomain. BACE1, beta‐site
amyloid precursor protein cleaving enzyme‐1 [Color figure can be viewed at wileyonlinelibrary.com]
10
|
MOUSSA‐PACHA ET AL.
Another essential feature of β‐secretase active site is the 10 seconds loop which is positioned near Ser10, in the
S3 pocket (Figure 4). When the 10 seconds loop adapts an open conformation, this allows for maximum binding of
substrate to the S3 pocket. The three entities, catalytic aspartic acid residues, β‐hairpin loop, and 10 seconds loop
together form a binding pocket for β‐secretase's substrate or inhibitor. When a ligand binds, this triggers the flap to
close which stimulates further interaction with the 10 seconds loop, generating a stable complex structure.
49
Another feature in the BACE1 structure is the presence of water molecules that is known as the special pocket,
which is not usually occupied by the ligand. The water molecule that is allocated in the middle of the catalytic site is
believed to have an essential role in the hydrolysis of peptide bonds.
41
The latest hypothesis related to the BACE1
mechanism of action suggested that one of the catalytic aspartyl residues acts as an acid/base sink. Kinetic studies
demonstrated that the basic pK
a
value for the Asp residue is 3.5 and that for the acidic residue feature a pK
a
value
of 5.2. Moreover, the best in vitro catalytic activity of the enzyme was obtained when the pH approximates to 4.5.
41
For complete activation, the enzyme acquires mono protonation in the active form (Figure 7).
3
The four oxygen
atoms of Asp32 and Asp228 of BACE1 active site are not equal owing to their different chemical environment,
FIGURE 6 The binding interactions of OM99‐2 with the active site of BACE1. OM99‐2 is the first BACE1
inhibitor that binds to eight amino acid residues in different subpockets. BACE1, beta‐site amyloid precursor
protein cleaving enzyme‐1
FIGURE 7 Mechanism of action of the catalytic aspartic acid residues. Water molecules have a vital role in facilitating
the hydrolysis of peptide bonds by the aspartic acid residues [Color figure can be viewed at wileyonlinelibrary.com]
MOUSSA‐PACHA ET AL.
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11
suggesting a possible set of distinct protonated states. Qualitative analysis of this state suggests that only the
mono‐and di‐deprotonated species are relevant for the design of potent inhibitor.
41
With these in mind, the effective inhibition of BACE1 requires an inhibitor that possesses a higher affinity to
the binding site of the enzyme when compared to the indigenous substrate. This form of competitive inhibition can
be achieved by maximizing the number of binding interactions between BACE1 and the inhibitor, with focus on
binding to the catalytic amino acid dyad.
50
The elongated active site of BACE1 allows for accommodating up to
11 amino acids of substrates. The 11 subpockets have a broad amino acid tolerance, but many central ones (such as
P1 and P1′) are hydrophobic in nature and accommodate hydrophobic side chains. This characteristic can be
advantageous in the development of BACE1 inhibitors with enhanced lipophilicity to improve their membrane
permeability and penetration of the BBB.
50
3.2
|
Classes of BACE1 inhibitors
3.2.1 |Peptidomimetic BACE1 inhibitors
Compounds in this class feature the presence of an amide bond or one of its isosteres.
51
Many transition‐state
bioisosters have been used as the main element for the design of aspartyl protease inhibitors including
hydroxyethyleneisostere‐, hydroxyethylamine‐, isophthalamide‐based inhibitors, and others like reduced
amide‐, statins, and norstatins‐as well as macrocyclic‐based inhibitors.
52
Hydroxyethylene isosteric inhibitors are the first class of BACE1 inhibitors to be developed. Designing a
hydroxyethylene‐based inhibitor with an oxazolylmethyl substituent at P3 position such as compound 1(Table 2),
led to a very potent peptidomimetic BACE1 inhibitor (K
i
= 0.12 nM), with high selectivity of more than 3800‐fold
over BACE2 and 2500‐fold over CatD.
53
Other structural modifications were performed to develop inhibitors with
Leu‐Ala isoster and isopthalamide moieties at P2 position.
54
Thus, incorporation of a hydrophobic group to this
skeleton at P3 position led to the formation of compound 2, where the (R)‐methyl benzylamide showed better
potency than benzylamide or (S)‐methyl benzylamide. Although this inhibitor possesses a slight selectivity against
BACE2 and CatD (28 and 37‐fold respectively), it possessed an excellent BACE1 IC
50
of 39 nM.
54
However, the
results of in vivo studies were encouraging, as the intraperitoneal injection of 8 mg/kg of compound 2resulted in a
30% reduction of Aβ40 brain levels in transgenic mice after 4 hours.
54
In other work, a series of hydoxyethylene‐
based compounds were synthesized with the aim to discover the potential interactions with BACE1 S1 and S3
binding subpockets. The most potent compound among the 30 compounds developed in this series was compound
3that exhibited a remarkable IC
50
value of 69 nM.
55
This compound possesses bulkier substituents on the
hydroxyethelene skeleton compared with other compounds in the same series, which indicated that the binding site
of the enzyme at P1 and P3 dispositions could accommodate such large moieties. Nonetheless, this promising
activity was not supported by the cell binding assay results that showed a very low percentage of inhibition (ca. 3%)
of Aβ. This weak activity might be due to the polar amide residues contained in this compound and its high
molecular weight which might be limiting factors that affected its cell permeability.
55
Other important work from Chang et al,
56
focused also on the design of potent BACE1 inhibitors based on the
hydroxyethylamine (HEA). For example, compound 4with a 3‐methoxybenzyl group at P1, and phenylalanine side
chain at P1′showed a subnanomolar IC
50
of 1.0 nM.
56,57
Furthermore, compound 4revealed a 39‐fold selectivity
for BACE1 over BACE2 and 23‐fold selectivity over CatD. Administration of 8 mg/kg of inhibitor 4in Tg2576 mice
showed a 65% reduction of Aβ40 levels. Other in vivo cognitive studies were performed on transgenic mice, where
the compound was given in a dose of 33.4 μg/day to four groups of different ages and different treatment periods.
The results were promising and revealed that the cognitive function in younger AD mice can be rescued by a partial
reduction in Aβformation and neuritic plaque. The same study indicated no detectable signs of toxicity or
accumulation of uncleared APP.
56
Another important hydroxyethylene bioisoster is compound 5, which was developed by the Beswick group. This
six‐membered ring, sultam derivative 5, exhibited a high BACE1 IC
50
and cellular Aβactivity
58
and a 44‐fold
12
|
MOUSSA‐PACHA ET AL.
TABLE 2 Peptidomimetic BACE1 inhibitors profile (IC
50
, selectivity, efflux ratio, and bioavailability)
Hydroxyethylene‐based Inhibitors BACE1 IC
50
BACE1 selectivity
Pgp efflux ratio Bioavailability Ref.Over CatD Over BACE2
K
i
= 0.12 nM > 2500 fold > 3800 fold ‐‐
39
K
i
= 1.1 nM 37‐fold 28‐fold ‐‐
40
69 nM ‐‐‐‐
41
Hydroxyethylamine‐based inhibitors
1nM 23‐fold 39‐fold ‐‐
42,43
(Continues)
MOUSSA‐PACHA ET AL.
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13
TABLE 2 (Continued)
Hydroxyethylene‐based Inhibitors BACE1 IC
50
BACE1 selectivity
Pgp efflux ratio Bioavailability Ref.Over CatD Over BACE2
4 nM 663‐fold 44‐fold ‐Low
44
55 nM 7.6‐fold ‐3‐
45
2 nM 100‐fold ‐2‐
45
Isophthalamide‐based inhibitors
15 nM ‐‐‐Low
46,48
18 nM ‐204‐fold ‐‐
25
2.5 nM 60‐fold ‐‐ ‐
51
(Continues)
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|
MOUSSA‐PACHA ET AL.
TABLE 2 (Continued)
Hydroxyethylene‐based Inhibitors BACE1 IC
50
BACE1 selectivity
Pgp efflux ratio Bioavailability Ref.Over CatD Over BACE2
0.32 nM > 1000 fold ‐‐ ‐
51
0.4 nM > 250 000 fold 42‐fold ‐Low
52
Note: Data is not available.
Abbreviation: BACE1, beta‐site amyloid precursor protein cleaving enzyme‐1.
MOUSSA‐PACHA ET AL.
|
15
selectivity for BACE1 over BACE2. The remarkable potency of this compound was believed to be due to the
presence of meta‐ethylamine residue resident in the S3 subpocket, hence enhancing the binding affinity in the
active site by interacting with the catalytic dyad. Unfortunately, compound 5showed low oral bioavailability in
transgenic mice studies. This was revealed following oral administration at a dose of 250 mg/kg two times daily that
led to only a 23% decrease in Aβ42 levels in the brain of the diseased mouse. Interestingly, in the same study, it was
also found that the administration of compound 5with P‐gp inhibitor reduced the Aβ42 levels by ca. 55%.
58
An elegant contribution from Rueeger et al is the design and synthesis of a novel class of cyclic hydroxyethylamine
(cHEA) BACE1 inhibitors employing the de novo design strategy. These compounds, this class of compounds should be
mentioned here, were found to possess good BBB permeability.
59
In this study, it was concluded that such a
framework might offer appropriate attachment vectors for direct extensions into the BACE1 subpockets. Thus, guided
by structure‐based optimization, a series of cHEABACE1 inhibitors containing 4‐hydroxy‐benzyl arms were developed
and showed greater BBB penetration and less P‐gp efflux compared with their acyclic HEA congeners. For example,
compound 6exhibited a BACE1 IC
50
of 55 nM with an efflux ratio of3. On the basis of these results, further structural
modifications were pursued to improve the potency, selectivity and metabolic stability, to deliver a highly potent
alkoxy‐substituted 4‐amino‐fluoro‐benzyl cHEA inhibitors, such as compound 7with a subnanomolar potency against
BACE1 (IC
50
= 2.0 nM) and more than 100‐fold selectivity for BACE1 over catD.
59
Isophthalamide‐based inhibitors are another transition‐state isosteres that have been developed as BACE1
inhibitors with increased BBB penetration while preserving the potency achieved by the HEA inhibitors. These
compounds have shown remarkable selectivity for BACE1 over other aspartic proteases.
60,61
For example, inhibitor
8exhibited considerable in vitro activity against BACE1 (IC
50
= 15 nM). Molecular modeling studies of
isophthalamide scaffolds revealed the formation of essential H‐bonding with the catalytic aspartates (Asp32 and
Asp228) by the hydroxyethylamine substituent, for example, 8. While the cyclopropyl moiety was found to be
directed toward the S1′subpocket of the enzyme active site. Furthermore, the right‐hand amide arm of the same
compound was found to be crucial appendage for the inhibition of BACE1 by forming two essential hydrogen bonds
with the enzyme's binding site (the amide NH with the Gly230 carbonyl group and the amide carbonyl with the NH
group of Gln73).
62
Unfortunately, compound 8showed poor BBB penetration, which encouraged other researchers
FIGURE 8 Cocrystal structure of compound 20 bound to BACE1. The X‐ray structure showed that the
3‐azaxanthene core interacts with Trp76 by crucial hydrogen bonds, while other hydrogen bonds are formed
between the oxygen of the dihydropyran and Tyr198, and between the pyridyl nitrogen and Ser229. BACE1,
beta‐site amyloid precursor protein cleaving enzyme‐1 [Color figure can be viewed at wileyonlinelibrary.com]
16
|
MOUSSA‐PACHA ET AL.
to design and develop new peptidomimetic analogs based on isophthalic acid scaffolds with the aim to enhance BBB
permeability. For instance, Al‐Tel and co‐workers used compound 8as a lead to design and synthesize new motifs
derived from isophthalic acid with enhanced pharmacodynamic properties as potential BACE1 inhibitors,
employing different structure‐based drug design strategies. The traditional medicinal chemistry strategies followed
in this study, such as rigidification, contraction, and bioisostere replacement led to the development of BACE1
inhibitors with high potencies.
39,63
Scheme 1 illustrates the main strategies utilized to design and develop a series
of BACE1 inhibitors with improved affinity and inhibition activity.
64
The most potent compound of this series
(compound 9), exhibited a BACE1 IC
50
of 18 nM, with enhanced selectivity toward BACE1 over BACE2.
39
FIGURE 9 Role of RIPK1 inhibition in inflammation and necroptosis. RIPK1 inhibition led to the disruption of
toxic activity of the resultant complexes which in turn reduced the inflammatory mediators and amyloid burden,
and improved memory function. RIPK1, receptor‐interacting serine/threonine‐protein kinase 1 [Color figure can be
viewed at wileyonlinelibrary.com]
N
H
HN
N
O
S
31
FIGURE 10 Structure of RIPK1 inhibitor. RIPK1, receptor‐interacting serine/threonine‐protein kinase 1
MOUSSA‐PACHA ET AL.
|
17
Another important initiative from Bjorklund et al who developed promising isophthalamide analogs, for
example, compound 10. Initially, compound 10 with an IC
50
of 2.5 nM and K
i
of 1 nM was prepared, however, the
low selectivity toward CatD (K
i
= 59 nM) was the main drawback of this inhibitor. Henceforth, the focus was shifted
toward the main difference between the S1′subpockets of BACE1 and that of CatD to optimize the potency and
improve the selectivity over CatD. In this context, SAR studies showed that the S1′pocket of BACE1 could
accommodate larger groups and form polar interactions, contrary to CatD S1′subpocket which can only engage in
hydrophobic interactions with the ligand. Based on this observation, the introduction of a small polar group like
methoxyl at P1′, provided the most potent inhibitor in this series, compound 11, which showed an increase in
potency (IC
50 =
0.3 nM) and highly improved selectivity against CatD of more than 1000 folds.
65
Related to the same group also developed compound 12 which is isophthalamide‐based inhibitors bearing a
1,3,4‐oxadiazole ester moiety. This compound was found to have an excellent potency against BACE1 with an IC
50
of 0.4 nM, in which both of the P2 and P3 arms were adjusted to increase the efficacy and cellular permeability.
However, it revealed moderated selectivity (42‐fold) against BACE2 and improved selectivity (more than 250,000‐
fold) against CatD.
66
Intraperitoneal administration of inhibitor 12 at a 100 mg/kg dose in mice resulted in a
moderate decline of Aβ
40
concentration (26%) levels after 4 hours, with a brain exposure of 1.8 μM. Interestingly,
time and dose‐dependent studies, using this compound, in rhesus monkeys displayed a 65% reduction of plasma
Aβ40 levels after 4 hours postinjection, a return of Aβ40 levels after 8 hours, and full recovery after 24 hours.
N
N
NH
2
O
HN
O
O
32
N
N
S
O
O
33
S
O
Cl Cl
34
R
O
X
35
FIGURE 11 Structure of GSK‐3βinhibitors
FIGURE 12 Aβo Role in Fyn kinase activation. Aβo are soluble Aβaggregates with synaptotoxic effect. They
interact with PrPC on the neuronal cell membrane activating a downstream signaling cascade via the nonreceptor
tyrosine kinase Fyn and generating cellular damage. Thus, studies suggested Fyn inhibition as a therapeutic
approach to suppress and minimize neuronal damage [Color figure can be viewed at wileyonlinelibrary.com]
18
|
MOUSSA‐PACHA ET AL.
Unfortunately, due to the extensive hepatic metabolism by CYP3A4 enzyme, the oral bioavailability of this
compound was found to be poor with less than 1% bioavailability upon 10 mg/kg oral dosing.
66
In conclusion, the last decade or so has witnessed the synthesis of many peptidomimetic‐based inhibitors,
particularly HEA inhibitors, but unfortunately, many of these peptidomimetics showed poor oral bioavailability,
short in vivo half‐life, limited BBB penetration, and low reduction of Aβlevels, which ultimately placed these
compounds in the back chamber of the moving train.
55
Although the isophthalamide class showed very promising
results, for example, compound 11, with BACE1 IC
50
of 0.32 nM, and more than 1000‐fold selectivity for BACE1
over CatD, however, none of these motifs made it to clinical trials. Overall, despite the tremendous efforts that
were made to design peptidomimetic‐based inhibitors, the majority of these inhibitors did not exhibit good
pharmacological properties. Nevertheless, these motifs furnished the way toward the design of other classes of
inhibitors with improved pharmacokinetic and pharmacodynamic parameters. The focus was therefore shifted
toward the next generations of BACE1 inhibitors, namely the nonpeptidomimetic inhibitors.
52
3.2.2 |Nonpeptidomimetic BACE1 inhibitors
The development of nonpeptidomimetic BACE1 inhibitors has been facilitated by the utilization of high‐throughput
screening (HTS) campaigns followed by the SAR development of the best hits. These inhibitors offered various
advantages over the peptidomimetic inhibitors, including improved metabolic stability. Moreover, nonpeptidomi-
metic inhibitors are smaller in size, which had improved BBB permeability and decreased P‐gp efflux ratio. Many
different classes of nonpeptidomimetic inhibitors were developed. A salient feature of these inhibitors is the
presence of an aminoazine residue embedded in their scaffold. The different classes of these inhibitors could be
seen in compounds that contain acyl guanidine‐,2‐aminopyridine‐, aminoimidazole‐, amino/iminohydantoin‐,
aminothiazoline and aminoxazoline‐, dihydroquinazoline‐, aminoquinoline‐, and aminopyrrolidine‐based Inhibitors
(Table 3).
66
The acyl guanidine scaffold attracted the attention of many research groups due to their highly distinctive
features compared to other nonpeptidomimetic BACE1 inhibitors. They showed high BACE1 potency with
remarkable pharmacokinetic properties including very low P‐gp efflux, which allowed these compounds to reach
advanced stages in clinical trials (Table 1).
42,67
It has also been found that, adding a pyrrolidine moiety to
O
O
Cl H
N
NN
ON
N
O
O
36
H
N
O
Cl
N
S
N
H
N
N
N
N
HO
37
FIGURE 13 Structure of Fyn kinase inhibitors
O
O
N
O
H
H
N
O
OOH
H
H
38 39 40
FIGURE 14 Structure of cannabinoid type 2 receptor agonists
MOUSSA‐PACHA ET AL.
|
19
guanidine‐containing compounds, such as compound 13, which is substituted at position 4 with N‐acyl pyrrolidine
group, resulted in the development of one of the most potent compounds compared with similar derivatives in the
same series with BACE1 K
i
value of 0.21 μM. Molecular modeling studies of this compound revealed a unique U‐
shaped conformation that directs the aryl group toward S2 subpocket of BACE1.
68
Furthermore, structure‐activity relationship (SAR) studies of these inhibitors revealed that the addition of an
ether linkage on the aryl group was highly tolerated, which encouraged researchers to pursue macrocyclization.
These initiatives were undertaken as a rigidification strategy to enhance the pharmacokinetic profile of these
motifs. Such a strategy resulted in an improvement of both in vitro and in vivo potency, with a significant reduction
in Aβformation. In the same series, compound 14 was the most active, with BACE1 K
i
value of 0.0032 μM and low
P‐gp efflux ratio of 2.3. Interestingly, the rigidification strategy led to macrocyclic derivatives that exhibited a great
selectivity over other acyclic derivatives in which compound 14 showed 700‐fold selectivity over CatD.
68
It is worth to mention that one of the highly effective compounds containing the guanidine scaffold is compound
15: MK‐8931 (verubecestat/Merck), which is the first BACE1 inhibitor to reach phase III clinical trials. This
compound has remarkable physiochemical properties, including improved oral bioavailability, cellular penetration,
and brain permeability. Results of in vitro studies showed that verubecestat exhibited potent activity against
BACE1 enzyme with an IC
50
of 2.2 nM. This could be explained from its binding modes in which strong hydrogen
bonds between the amidine moiety of verubecestat and the BACE1 catalytic dyad were obvious in its co‐crystal
structure. Moreover, verubecestat showed high selectivity for BACE1 when studied on other aspartyl proteases,
with more than 45 000‐fold selectivity over CatD, among others. Furthermore, the in vivo data support its efficacy
for the management of AD, as the administration of a single oral dose of 10 or 30 mg/kg in rats, significantly
reduced the cerebrospinal fluid (CSF) and cortical Aβ40.
69
Unfortunately, all of these promising findings were
overthrown by the latest results announced in May 2018, which showed the failure of verubecestat to reduce the
cognitive decline in 1958 enrolled patients, along with manifested adverse events.
70
Another important guanidine‐based derivative that reached phase III clinical trials is compound 16: E2609
(elenbecestat/Eisai, Biogen). This bicyclic aminodihydrothiazine substituted compound is similar in structure to the
previously mentioned compound 15. It showed a K
i
value of 27 nM and highly reduced the Aβlevels of the CSF and
SCHEME 1 Various design strategies utilized to synthesize a series of potent BACE1 inhibitors based on
isophthalic acid motif. Rigidification, contraction, and bioisostere replacement strategies have been used to develop
inhibitors with improved binding affinity
20
|
MOUSSA‐PACHA ET AL.
TABLE 3 Nonpeptidomimetic BACE1 inhibitors profile (IC
50
, selectivity, efflux ratio, and bioavailability)
Guanidine and it's analogs BACE1 IC
50
BACE1 Selectivity Pgp
efflux
ratio Bioavailability Ref.Over CatD
Over
BACE2
N
N
H
N
Ph
O
NH
2
Cl
N
H
O
Cl
13
0.21 μM‐‐Low ‐
54
N
N
H
HN
Cl
Cl
O
NH
O
O
H
2
N
14
0.0032 μM 700‐fold ‐Low
(2.3)
‐
54
S
N
N
N
H
O
N
F
FNH
2
O
O
15
2.2 nM > 45 000 fold ‐Low High
55
K
i
=27nM ‐‐‐‐
8
N
S
N
HN
N
O
F
H
2
N
17
‐‐ ‐‐‐
8
Amino/iminohydantoin‐based Inhibitors
N
Cl
N
N
H
HN
O
18
K
i
=21nM 350 ‐Low Good
57
N
N
H
HN
O
N
19
K
i
= 5.4 nM 7500 ‐Low Excellent
57
Aminothiazoline and aminooxazoline‐based
Inhibitors
ON
F
O
NF
N
O
H
2
N
20
0.3 nM ‐‐2.2 ‐
58
N
O
HN
O
N
Me
CF
3
NC
F
H
2
N
21 12 nM ‐‐1.9 68%
59
Note: Data is not available.
Abbreviation: BACE1, beta‐site amyloid precursor protein cleaving enzyme‐1.
MOUSSA‐PACHA ET AL.
|
21
plasma in rodents. Another aminoazine derivative is compound 17, known as JNJ‐54861911 (atabecestat/Janssen).
This aminodihydrothiazine‐containing compound proved to be very successful in reducing Aβlevels, which reached
up to 95% reduction after dosing in healthy volunteers. However, this compound raised safety concerns in phase II/
III clinical trials, which led to the discontinuation of these trials.
8
A promising chloropyrdine analog with
iminohydantoin scaffold (eg, inhibitor 18) was successfully developed. It showed good selectivity for BACE1
(350 fold over CatD) and potent BACE1 inhibitory activity (K
i=
21 nM). Further modifications aimed to improve the
ligand‐binding affinity in BACE1 subpockets, which was achieved by replacing the chloro‐substituent with a
propenyl group, in which the linearity of the substituent helped to form stronger interactions with the S3 pocket.
This enhancement in binding affinity was reflected on the potency, which was increased five folds more than that of
a similar chlorinated analog (inhibitor 17) with a K
i
value of 5.4 nM for the newly developed inhibitor 19.
Interestingly, the propenyl substituent improved the selectivity over CatD up to 7500 folds. On the other hand, the
oral administration of compound 19 demonstrated excellent bioavailability, which has been shown to be higher
than that found for compound 18. These modifications have therefore resulted in a more potent compound with a
better pharmacokinetic profile.
71
Other classes of amino azines inhibitors are compounds containing the amino‐oxazoline and xanthene cores,
which showed a remarkable inhibition potency against BACE1. However, these compounds were found to
exhibit high P‐gp efflux ratio.
72
Functionalization of the xanthene core led to compound 20 possessing a
3‐aza‐2‐fluoroxanthene moiety reported by Cheng et al. Inhibitor 20 is a highly effective BACE1 inhibitor that
significantly reduced the brain and CSF Aβlevels in both rats and nonhuman species.
72
X‐ray costructural studies of
inhibitor 20 bound to BACE1 showed that the 3‐azaxanthene core formed strong hydrogen bonding interactions
with Trp76. Other hydrogen bonds formed between the oxygen of the dihydropyran and Tyr198. The pyridyl
nitrogen formed an extra hydrogen bond with Ser229 (Figure 8).
72
Another expansion of these amino azines scaffolds was developed by including the substituted aminoxazines,
which showed potent activity against BACE1. For example, compound 21 possesses an IC
50
of 12 nM and cellular
IC
50
of 2 nM.
73
It also showed a dose‐dependent reduction in Aβ40/42 levels in the brain of mice and revealed a
good oral bioavailability in rats (68%).
73
In Summary, many classes in this family were developed as potent BACE1 inhibitors, from which, compound 15:
MK‐8931, with an IC
50
value of 2.2 nM, is among the guanidine derivatives, which reached phase III clinical trials
and showed optimum properties including potency, bioavailability, and selectivity. It is noteworthy to mention that
many inhibitors from the aminothiazoline and aminoxazoline family showed potent activities against BACE1 with
IC
50
s in the nanomolar and subnanomolar range. Despite the success in producing potent inhibitors of BACE1 from
this family, the literature lacks detailed data regarding their selectivity profile. Furthermore, it is worthy to note
that the most potent BACE1 inhibitors in this class, which reached clinical trials, were recently revoked due to lack
of clinical efficacy.
8,70
3.2.3 |Naturally‐occurring BACE1 inhibitors
Natural products estate plays an essential role in the discovery of medicinal agents. The last decades have
witnessed the approval of many drugs of natural origin.
74
Moreover, management of complicated diseases such as
AD may require natural materials that contain various natural compounds with targeting multiple proteins rather
than a single‐target synthetic compound.
75
Therefore, phytochemicals enjoy high 3D‐content and diverse molecular
scaffolds that can serve the clinical needs, besides their safety profile compared to their synthetic counterparts may
offer another advantage.
76
During the development of BACE1 inhibitors of natural products origin, many studies directed the attention
toward naturally occurring polyphenolic compounds, like flavonoids, particularly polymethoxyflavones extracted
from black ginger (Kaempferia parviflora [KP]). KP plant was primarily known to have antioxidant, anticarcinogenic,
and antifatigue properties.
77
However, its extract consists mainly of three major components, namely
22
|
MOUSSA‐PACHA ET AL.
polymethoxyflavones, 5,7‐dimethoxyflavone (DMF), 5,7,4′‐trimethoxyflavone (TMF), and 3,5,7,3′,4′‐pentamethox-
yflavone (PMF), which showed considerable BACE1 inhibitory activity, with an insignificant effect on α‐secretase
and other serine proteases. Youn et al carried out an in silico study utilizing a human BACE1 with nonpeptidyl
polymethoxyflavones, to assess their mode of binding.
78
These results demonstrated the strong ability of KP
polymethoxyflavones to inhibit BACE1 in a dose‐dependent manner and revealed the H‐bond interactions between
the polymethoxyflavones and BACE1. For example, TMF (compound 22) exhibited the most potent BACE1
inhibitory activity with an IC
50
of 36.9 μM, followed by DMF (compound 23) (IC
50 =
49.5 μM) and PMF (compound
24) showed the least potency with an IC
50
of 59.8 μM.
78
To rationalize these findings from the chemical structure
point of view, suggest that BACE1 inhibition resulted from the common methoxyl groups at C5 and C7 in ring A.
Furthermore, a methoxyl group at C4′in ring B would enhance the activity, while addition of methoxyl groups at C3
and C3′reduced the BACE1 activity (TMF > DMF > PMF). Interestingly, these compounds were reported to be
noncompetitive BACE1 inhibitors, since they interact with the enzyme by binding to the allosteric sites. In contrast,
synthetic peptidomimetic BACE1 inhibitors bind directly to the active site, therefore, they are competitive
inhibitors.
79
A supportive study was done by Mekjaruskul et al in rats, which indicated that DMF, TMF, and PMF
natural products were detected in the rat brain, indicating their ability to cross the BBB.
80
Other triflavonoids derivatives, isolated from Selaginella doederleinii (Selaginellaceae) plant, have been
investigated and showed promising BACE1 inhibitory activity. S. doederleinii is commonly used in Chinese herbal
medicine as anti‐inflammatory, anticancer, and cardioprotective agent.
81
Zou et al have successfully isolated
several triflalvonoids, for example, selagin triflavonoids 25, which possesses trimeric scaffolds isolated from S.
doederleinii herb. An in vitro study using a fluorescence resonance energy transfer (FRET) technique displayed that
compound 25 was the most potent BACE1 inhibitor with an IC
50
of 0.75 μM, while compound 26 was the weakest
inhibitor (IC
50 =
46.99 μM). Moreover, SAR study suggested that a selagin triflavonoid with a naringenin unit
(compound 25) rather than an apigenin unit (compound 26) is preferred, and have enhanced activity.
81
Another study was performed on Leea indica plant by Hosen et al, where 40 molecules were isolated from
different parts of the plant.
82
L.indica is a huge shrub and its leaves were used in folk medicine as antispasmodic,
anticancer, and antidiarrheal remedy.
83
Virtual screening studies on the isolated compounds have identified two
triterpenes molecules, ursolic acid (compound 27) and lupeol (compound 28) which exhibited higher BACE1 binding
affinity. SAR studies revealed that the binding of these triterpenes in the BACE1 active site is driven by the
formation of hydrogen bonds between ursolic acid and the Asn233 and Thr232 residues, with weak contribution
from hydrophobic interactions, whereas lupeol interacts with Gly11 residue by hydrogen bonding and forms much
stronger hydrophobic interactions with the active site. Furthermore, although both compounds formed
hydrophobic interactions with Tyr71 residue at the flap region, however, none of them was able to interact with
the catalytic aspartic acid residues (Asp32 and Asp228). Theoretical calculations of the PK values have shown that
lupeol could cross the BBB more efficiently than ursolic acid.
82
Moreover, other studies indicated that lupeol have
neuroprotective property.
84
It has also been reported that lupeol inhibits BACE1 with an IC
50
value of 5.12 μM.
82
In another study conducted by Zhu et al,
85
a library of marine natural products with diverse molecular scaffolds
were studied and the results showed anti‐AD effects with two steroidal extracts isolated from the U.unicinctus.
86
Using the FRET approach, the EC
50
values of these compounds when tested against BACE1, have identified
hecogenin (compound 29) cholest‐4‐en‐3‐one to possess a value of 116.3 μM, while that of cholest‐4‐en‐3‐one
(compound 30) was 390.6 μM. In comparison with the more potent synthetic BACE1 inhibitors, the naturally
derived hecogenin and cholest‐4‐en‐3‐one have lower molecular weights that would allow them to effectively
penetrate the BBB. Furthermore, they are derived from edible marine sources, which gives an indication of their
safety profile.
85
The characteristic features of the mentioned naturally derived products that were extracted from various
plants and organisms are summarized in Table 4. Despite their low activities against BACE1, preliminary findings
suggest that their anti‐AD effect could offer beneficial advantages over the synthetic leads in terms of their safety
profile, as one of the major drawbacks of the BACE1 inhibitors entered clinical trials. To date, most of the studies
MOUSSA‐PACHA ET AL.
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23
TABLE 4 Naturally‐derived BACE1 inhibitors profile
Compound Natural Source Chemical classification BACE1 IC
50
Ref.
O
OCH
3
OCH
3
H
3
CO
O
22 (TMF)
Kaempferia parviflora (black ginger) Flavonoids (polymethoxyflavones) 36.9 μM
64
O
OCH
3
H
3
CO
O
23 (DMF)
Kaempferia parviflora (black ginger) Flavonoids (polymethoxyflavones) 49.5 μM
64
O
OCH
3
H
3
CO
O
OCH
3
OCH
3
24 (PMF)
Kaempferia parviflora (black ginger) Flavonoids (polymethoxyflavones) 59.8 μM
64
O
O
O
O
OH
O
OHOH O
OH
OH
OH
O
OH
OH
25 Selaginella doederleinii Flavonoids (triflavonoids) 0.75 μM
67
Selaginella doederleinii Flavonoids (triflavonoids) 46.99 μM
67
HO
H
H
H
O
OH
27 (Ursolic acid)
Leea indica Triterpenes ‐
68
(Continues)
24
|
MOUSSA‐PACHA ET AL.
TABLE 4 (Continued)
Compound Natural Source Chemical classification BACE1 IC
50
Ref.
HO H
H
H
28 (Lupeol)
Leea indica Triterpenes 5.12 μM
68
HO
H
H
H
O
O
H
H
H
O
H
29 (Hecogenin) Urechis unicinctus Steroids EC
50
= 116.3 μM
71
Urechis unicinctus Steroids EC
50
= 390.6 μM
71
Note: Data is not available.
Abbreviation: BACE1, beta‐site amyloid precursor protein cleaving enzyme‐1.
MOUSSA‐PACHA ET AL.
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25
conducted on natural compounds were in vitro assays only; therefore, advanced in vivo studies are needed to
address several questions including their mechanism of action and their clinical effect.
4
|
FAILURE OF BACE1 INHIBITORS: LESSONS TO THE FUTURE
For many years now, targeting the amyloid hypothesis to tackle AD has been the cornerstone for many drug
developers. The extensive research has resulted in the development of many potent BACE1 inhibitors; some of
them reached different phases of clinical trials. Having a group of BACE1 inhibitors in advanced clinical stages
was by itself a remarkable achievement, and raised the level of researchers’expectations toward the belief that
a possible solution for AD riddle can be achieved by BACE1 inhibitors which may offer a breakthrough therapy
of this mystery.
42
However, the latest results of some of the BACE1 inhibitors in clinical trials brought
opposing findings that set back the hopes on this target. Among the promising compounds that were developed
by Merck pharmaceutical company and believed to be the major hope in the battle against AD, is the MK‐8931
(verubecestat), which belongs to the nonpeptidomimetics guanidine family of BACE‐1 inhibitors. Despite the
remarkable results for its potency (IC
50
= 2.2 nM), selectivity, pharmacokinetic and physiochemical properties,
Merck has recently announced discontinuing phase III clinical trial conducted on 1958 patients with mild‐to‐
moderate Alzheimer's disease.
70
The main reason behind this failure is the lack of efficacy, as patients on
verubecestat did not show improvement of their cognitive function compared with the placebo group despite
the ability of verubecestat to reduce Aβlevels in the brain and cerebrospinal fluid.
70
Moreover, another
pertaining cause is the experienced adverse effects associated with verubecestat use, such as futility, rashes,
falls and injuries.
70
Furthermore, it was suggested that the failure of verubecestat to achieve the desired goal
could be attributed to the fact that reducing the level of Aβproduction is of no clinical benefit after the
patients are diagnosed with dementia, as the accumulation of Aβhappens years before symptoms of dementia
appear in AD patients. Another possible explanation for the failure of BACE1 inhibitors in reducing AD
progression might be due to the complexity of the genetic factors responsible for AD disease progression and
the inability of the amyloid hypothesis alone to explain the progression of the disease.
70
One of the famous
examples of BACE1 inhibitors that attracted the attention of many researchers is the failure of JNJ‐54861911
(atabecestat) to show significant clinical efficacy. This aminodihydrothiazine‐containing derivative was tested
on a group of asymptomatic patients with high risk for AD, in a multicentered trial which enrolled 1650
individuals.
30
Initially, the results were encouraging as atabecestat was capable of achieving a 95% reduction in
Aβproduction after dosing in healthy volunteers. However, on May 17, 2018, it was decided to hold the trial
due to an abnormal elevation in liver enzymes among 600 of the participants.
30
These observations for the
progress of BACE1 inhibitors across different clinical trials clearly indicate that safety was the major barrier
against the success of many BACE1 inhibitors. For instance, two compounds developed by Eli Lilly, LY‐2811376
and LY‐2886721 were halted from further progress in clinical trials due to signs of liver injury. Moreover,
BI1181181 developed by Boehringer Ingelheim is a compound that succeeded in reducing Aβbrain levels and
passed two‐phase I clinical trials. However, once again safety was the main reason that ruled out BI1181181
from the market and forced Boehringer Ingelheim to terminate its development in July 2015. Furthermore, due
to unrevealed causes, AZD‐3839 from AstraZeneca, and RG‐7129 from Roche were also terminated in clinical
trials.
30
Henceforth, from the stated examples it is observed that many promising BACE1 inhibitors shared the same
outcome when it comes to clinical application, whereby they failed to reach the sought‐after goal in managing AD.
Therefore, it becomes indispensable to carefully examine what are the factors behind this failure and to seek
answers and solutions to whether the failure lies in utilizing BACE1 as a target for AD or there are missing
elements that need to be considered when designing BACE1 inhibitor. Herein, we report some of the possible
hypothesis in the following sections.
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4.1
|
Structure‐based failure
One of the many factors to procure potent BACE1 inhibition stems from optimizing the interaction
between BACE1 and its ligands; however, this interaction is of unique nature, as it can be described as a
dynamic interaction, whereby several structural features need to be carefully assessed. Hence, taking a
closer insight toward the dynamics of the ligand‐BACE1 interaction via different tools would be of the
essence and can provide solutions to enhance the design of BACE1 inhibitors while explaining the failure of
the present inhibitors.
For instance, a study by Gueto et al was performed to serve this goal where they have measured the
residue‐ligand interaction energies of 112 amino acid in BACE1 active site using the PM7 semi‐empirical
technique, with different inhibitors from the hydroxyethylamine family that gave rise to many powerful
BACE1 Inhibitors of favorable pharmacokinetics, yet they did not provide clinical value.
87
The study revealed
that hydroxyethylamine inhibitors have six anchor points when binding to BACE1; Asp93, Asp289, Thr292,
Thr293, Asn294, and Arg296.
87
The binding to these anchor points accounts for 45% of the total BACE1‐
inhibitor interaction. Thus, designing inhibitors that are capable of forming those vital anchor point
interactions with BACE1 and maintaining this interaction over time is crucial to yield the best possible
inhibitory activity. It was observed that the protonation status of hydroxyethyl amines could be shifted with
time resulting in loss of essential interactions with BACE1 residues shifting the flap confirmation from the
active (closed) back to the open form.
88
Therefore, this shift in the flap confirmation can explain how some
HEAs derivatives would fail to inhibit the BACE1 activity in real time. Furthermore, the quantitative analysis
performed by Geuto et al for the enzyme and the ligand‐enzyme distances illustrated that the structural
modifications of the ligand head and tail would make a fundamental difference and affect the flap closure. All
of these factors are to be considered when designing a successful HEAs BACE1 inhibitor.
The protonation status of the catalytic dyad residues Asp32 and Asp228 in the presence of the inhibitor can
also be a detrimental factor to a potent BACE1 inhibition, by augmenting and optimizing the ligand‐enzyme
interaction. It is well perceived that the best activity of the enzyme is achieved in an acidic environment with a pH
of 4.5, which provides the optimal medium for the acid‐base interaction between the catalytic dyad residues with
the ligand.
89
However, the protonation status of the dyad while the inhibitor is in place is not well established.
Kocak et al investigated all the possible protonation status of the dyad amino acids in the presence of potent acyl
guanidine‐based inhibitor, with the aim to determine the most stable and favorable protonation status.
90
The
results of molecular dynamic simulations showed that when the ligand‐containing NH
2
warhead is protonated (at
pH 4.5), the di‐deprotonated status of the dyad is the most preferred, and is 14 kcal/mole more stable than all other
presumed options.
90
A similar positive finding was confirmed when the ligand was unprotonated. Thus, one should
consider the protonation status, when designing BACE1 inhibitors, since it might be a pivotal player to stabilize
their interaction with the enzyme.
90
Another important milestone that must be carefully considered when engineering a structure for BACE1
inhibition is the selectivity toward BACE1 over other homologs proteases like BACE2, and CatD as the lack of
specificity can result in significant adverse effects. Despite the structural similarity between, for instance, BACE1
and BACE2 as the two proteases share 64% homology in the amino acid sequence, however, their biological
functions are different.
91
Therefore, it is pivotal to explore the key elements that govern BACE1 selectivity.
Thorough investigations including alignment, molecular dynamic, and docking studies were conducted on four
selective BACE1 inhibitors.
92
These studies showed that the main factor for selectivity is the hindrance that can be
easily fitted and occupied in BACE1 active site but that is not possible in the small catalytic cavity of BACE2,
whereas the large active site of CatD does not offer optimum number of interactions between the ligand and the
enzyme.
92
In addition, the formation of strong electrostatic bonds with Asp32, Asp288 in BACE1 cleft along with
multiple hydrogen bonds, and the Van der Waals interactions, correctly orient the inhibitor in the BACE1 active
site, as it has a different shape when compared to similar proteases.
92
MOUSSA‐PACHA ET AL.
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27
4.2
|
The selectivity of BACE1 inhibitors
Tackling the amyloid cascade hypothesis via the inhibition of BACE1,
93
have recently resulted in reports raising
safety concerns and adverse side effects.
70
These alarming effects can be better explained by exploring the
molecular mechanism through which BACE1 processes the amyloidogenic substrate APP. It was reported that
BACE1 is not entirely selective toward targeting solely the amyloidogenic substrate, in fact, it was even noticed
that BACE1 has a greater affinity toward the cleavage of the nonamyloidogenic substrates like neuregulin‐1
(NRG1).
93
NRG1 has various vital roles in developmental processes, among which is neuronal myelination, in
addition, BACE1 is needed to activate NRG1.
94,95
Hence, BACE1 inhibitor will not only abolish BACE1 role in
processing APP, which is needed to tackle AD, but it will also prevent the cleavage of the nonamyloid substrates
that are required for their function. At the molecular level, it was established that the cleavage of APP by BACE1
happens in an early endosome, where both the substrate and the enzyme undergo endocytosis.
93
On the other
hand, it was reported that BACE1 processing of the nonamyloidogenic substrates is not endocytosis‐dependent.
93
Therefore, this difference in the subcellular compartmentalization forms a fundamental factor that can be exploited
to create selective BACE1 inhibitors, which target only the endosome containing BACE1 and its amyloidogenic
substrate APP, while leaving BACE1 processing of the nonamyloid substrates undisturbed, to avoid unwanted
adverse effects. In fact, such tactics have been utilized by designing a sterol linked BACE1 inhibitor,
96
where the
sterol linkage can guide the molecule to the lipophilic endosome compartment sparing the free BACE1 from
cleaving NRG1.
97
Sterol linked inhibitor was more efficient in reducing Aβproduction and targeting BACE1 activity
compared with the free inhibitor in cell culture.
96
Moreover, this success was confirmed in vivo by demonstrating
improved safety profile, where treating transgenic Drosophila model with sterol linked BACE1 inhibitor improved
survival rates of the Drosophila larvae compared with control.
96
In addition, the sterol linked inhibitor efficacy was
highlighted in an in vivo study performed on APPs/PSDE9 mice which were injected with either solvent, free
inhibitor, or sterol linked inhibitor to the hippocampus. The sterol linked BACE1 inhibitor‐treated group showed
the most efficient Aβreduction.
98
Such findings might pave the way toward adopting new strategies to minimize
the side effects associated with BACE1 inhibition.
4.3
|
BACE1 inhibitors and gender variations: differences in brain metabolites
AD occurs more in females than males, where two‐thirds of patients with AD are women.
99
The exact reason for
this gender variation is not well understood and rather controversial. Reports indicated the decline in the
neuroprotective steroidal hormones like estrogen. However, clinical data in support of its relation to AD remains
obscure.
100
Moreover, well‐known crosstalk between AD genetics and gender might also explain the higher
females’susceptibility to the disease, where APOE‐ε4 allele attributes to a higher risk for AD in females compared
with males.
101
In addition, pathological brain changes occur at an earlier age in females compared with males during
the period of the disease progression. A study with transgenic APP mutant mice showed that female mice begin to
show a higher rate of Aβaccumulation at an earlier age (6‐9 months) compared with males.
102
In vivo studies
indicated that metabolic profile is also prone to gender‐specific regulation, where it is found in APP/PS1 mice
model that the degree of brain metabolites alteration is more significant in females compared with males.
103
Another study conducted by Pan et al,
104
confirmed the gender‐based metabolic variation in vivo, on a different
mice strain, where they have used PLB4 mice, a specific strain that has been prone to human BACE1 knock in to
mimic the amyloidogenic AD pathology in humans.
104
In this study, female mice were grouped into two categories
on bases of age, then the PLB4 female mice and the wild type group were prone to metabolic profiling using LC‐MS/
MS.
104
It was then concluded that the older female PLB4 mice group had the most alteration in their brain
metabolic profile including 21 metabolites among which are; lysophosphatidylcholines, creatinine, sphingomyelin,
and leucine.
104
Thus, this study highlights that overexpression or upregulation of BACE1 interferes with the brain
metabolites regulation in a gender‐specific manner, which brings to the forefront the importance and the need to
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MOUSSA‐PACHA ET AL.
conduct specific analysis on the function and the fate of those altered metabolites upon BACE1 knock in and
inhibition. Indeed, a vital link might be revealed between gender, BACE1, and brain metabolite profiles that can
guide and specify the criteria where BACE1 inhibition would yield the best results.
4.4
|
BACE1‐inhibitors effects on the synapse structure and functions
The accumulation of Aβplaques in the synapse can result in synaptic impairment and contribute to AD
abnormality.
105
Nonetheless, it was also noted that BACE1 cleavage of APP could induce synaptic dysfunction,
independent from Aβaccumulation.
98
Hence, it is important to observe the effect of APP on synapse function and
how it can be regulated by BACE1 activity. In a study performed by Nigam et al,
106
immunoblotting demonstrated
that reduction in BACE1 activity could result in the accumulation of full‐length APP in the synapse of BACE1−/−
mice.
106
This intriguing observation offers a possible explanation to the ascending reports on safety concerns and
unwanted side effects arising from the use of BACE1 inhibitors in clinical trials, which resulted in halting such
trials.
106
In addition, a fundamental concept was highlighted in this study, in that the accumulation of full‐length
APP was only induced by complete BACE1 inhibition, whereas, partial inhibition did not have the same effect.
106
Therefore, controlling the dose of BACE1 inhibitor is a determinant player to combat AD successfully. It is
suggested that giving the lowest dose that would be effective in partially reducing BACE1 activity while still
conserving the synaptic function might be the ideal approach. Likewise, it was illustrated by an in vivo study that
managing the dose of BACE1 is crucial to avoid unwanted synaptic damage.
107
According to this report, the
administration of a high dose of BACE1 inhibitor affected synaptic function and plasticity in mice.
107
Nonetheless,
another hypothesis was brought to the forefront to correlate BACE1 inhibition to synaptic dysfunction other than
the impact of BACE1 on APP processing. Zhu et al
108
suggested that BACE1 inhibition induce synaptic impairment
via seizure protein 6 (SEZ6), which is one of the neuronal transmembrane proteins that are selectively cleaved by
BACE1 to produce the soluble SEZ6 and C‐terminal fragment.
108
Based on previous studies, it was reported that
knockout of SEZ6 in mice would result in physiological features that mimic those occurring in patients with AD,
such as, memory impairment, and dendritic spinal density reduction.
109
Therefore, Zhu et al tried in their work to
explore whether BACE1 inhibition is causing synaptic dysfunction due to perturbation in SEZ6 function. Thus, it
was demonstrated that prolonged BACE1 inhibition using potent inhibitor like NB‐360 was only causing reversible
spinal density reduction in wild type mice (control) while such effect was not seen in SEZ6 knockout mice group.
108
Moreover, synaptic impairment caused by BACE1 inhibition was prevented by knocking out SEZ6 from matured
neurons.
108
The results of the Zhu group have therefore confirmed that indeed SEZ6 is associated with synaptic
structural and functional impairment induced by BACE1 inhibition, and this change is reversible and dose‐
related.
108
Since synaptic side effects are found to be dose dependent, this raised the question of whether the
dose reduction of BACE1 inhibitors would be sufficient to manage AD. In fact, according to a study conducted on
BACE1 + /−mice, 40% reduction in Aβplaques was achieved with 50% inhibition of BACE1 without causing
synaptic adverse effects.
110
Thus, these preliminary findings suggest that partial BACE1 inhibition would still be
effective on AD patients who did not reach advanced stages with Aβplaques saturation.
5
|
ALTERNATIVE INTERVENTIONS TO PREVENT AβACCUMULATION
BY IMMUNOTHERAPY
As mentioned previously, AD is a neurodegenerative disorder that is characterized by the accumulation of
misfolded protein aggregates (Aβdeposits) in which they eventually lead to synaptic toxicity and neuronal loss.
111
Therefore, the mainstream in the development of AD treatment is directed against the Aβpeptide. One of the most
attractive and currently tested anti‐Aβapproaches is immunotherapy, particularly, passive immunotherapy which
involves the direct administration of external antibodies. Both active and passive immunization resulted in
MOUSSA‐PACHA ET AL.
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29
increased Aβdeposits clearance in humans and AD transgenic mice, but unfortunately, several agents have failed to
improve cognitive functions and resulted in serious adverse events.
112
Moreover, initial clinical trials of active
vaccination have reported cases of meningoencephalitis and studies were therefore terminated,
113
whereas
preclinical trials of passive immunization have displayed promising results.
114
Consequently, the safety concerns of
active immunization have shifted the attention toward devoting efforts to passive immunotherapy.
112
The approach of targeting Aβthrough passive immunotherapy attracted increasing attention. This strategy is
based on a mechanism called peripheral sink hypothesis, where the exogenous antibodies recognize, clear, and
reduce the concentration of Aβin the periphery through capturing these secreted Aβmolecules in blood
circulation. Thus, disrupting the Aβconcentration between the CNS and plasma and this concentration gradient
was found to promote the release of Aβfrom the brain.
115
In addition, these therapeutic antibodies have different
epitopes and vary in their detection and binding affinity to several Aβspecies (monomers, oligomers, protofibrils,
and fibrils).
116
AD was the cornerstone of immunotherapy research over the past 15 years.
111
Different monoclonal
antibodies (mAbs) have been designed and engineered to recognize different Aβconformations, and introduced
into clinical trials. However, the results from testing therapeutic mAbs were mystifying, since some have failed
and showed a lack of efficacy and have many side effects. Others have boosted the experience in improving and
developing better candidates,
112
beside others that showed enhanced Aβclearance.
117
According to many
reports, the stage of initiating the intervention in clinical trials is very critical, since targeting Aβin early stages of
AD or prophylactically may exhibit better impact than in late stages of AD.
118
Table 5, summarizes many
of these engineered antibodies including bapineuzumab, solanezumab, ponezumab, gantenerumab, aducanumab,
and crenezumab.
Bapineuzumab (AAB‐001, Pfizer/Janssen Pharmaceuticals) is an immunoglobulin (Ig) G1 Aβtargeting mAb,
developed from the humanization of murine mAb 3D6. Bapineuzumab stabilized by hydrogen bonds with five
residues at the N‐terminus of Aβ, and it is selectively recognized and clear both fibrillary and soluble Aβspecies.
112
It is the first mAbs that enters clinical trials after the discontinuation of AN1792 (the first active immunotherapy
for AD) trial.
113
Treatment with different doses of bapineuzumab was tested in participants with mild to moderate
AD to asses PK, safety, and tolerability profile. Based on these observations, bapineuzumab successfully reached
phase III clinical trial.
119
However, all bapineuzumab studies after concluding the results were terminated in August
2012,
112
due to the evidence of low efficacy and increased the occurrence of magnetic resonance imaging (MRI)
abnormalities, known as amyloid‐related imaging abnormalities attributed to edema or effusion (ARIA‐E) with high
doses of bapineuzumab and APOE‐ε4gene carriers.
120,121
Another first‐generation Aβpassive immunotherapy is solanezumab (LY2062430, Eli Lilly), an IgG1 mAb that is
humanized from the parent murine antibody m266. Solanezumab targets the residues 16 to 26 at the middle region
of Aβpeptide and has the ability to recognize the soluble monomers but not the fibrillary Aβspecies. Preclinical
studies in transgenic PDAPP mice (overexpress human amyloid precursor protein V717F) proved the ability of mAb
m266 to increase the clearance of soluble Aβspecies without binding the amyloid plaques.
112
Subsequently,
solanezumab exhibited an excellent safety profile in phase I and II trials, but unfortunately, no improvement in
cognitive functions was observed.
111
In phase III study, some clinical improvement resulted after months of
treatment in mild patients with AD, however, solanezumab failed to meet the primary outcomes and studies have
recently discontinued.
122
Nonetheless, the good safety profile of solanezumab was the main courage to currently
run prevention trials.
123
Ponezumab (PF‐04360365, Pfizer) also belongs to the first‐generation agents, a humanized IgG2 antibody that
binds the residues 30 to 40 at the C‐terminus of Aβ40. Comparing it with the other IgG1 mAbs, IgG2 have lower
tendency to stimulate the immune effector function.
124
Ponezumab entered phase I studies and displayed evidence
of safety and tolerability in mild to moderate patients with AD, without signs of ARIA.
112
Yet, the lack of clinical
efficacy was the reason to terminate the studies after phase II trial.
125
Consequently, studies over second generation anti‐AβmAbs have taken place due to the disappointing
observations from the first‐generation mAbs. Gantenerumab (RG1450/RO4909832, Hoffman‐La Roche), is the first
30
|
MOUSSA‐PACHA ET AL.
TABLE 5 Anti‐Aβmonoclonal antibodies in clinical trials for AD
Antibody name/code mAb type Epitope Aβspecies Clinical status Company
Refer-
ence
Bapineuzumab (AAB‐001) Humanized IgG1 Soluble and fibrillar forms N‐terminus (residues 1‐5) Phase III ‐
terminated
Pfizer/Janssen
105
Solanezumab (LY2062430) Humanized IgG1 Soluble monomers Mid domain (residues 16‐26) Phase III ‐
terminated
Eli Lilly
108
Ponezumab (PF‐04360365) Humanized IgG2 Soluble and aggregated
forms
C‐teminus (residues 30‐40) Phase IIa ‐
terminated
Pfizer
111
Gantenerumab (RG1450,
RO4909832)
Human IgG1 Fibrillar forms N‐terminus (residues 3‐12) and mid
domain (residues 18‐27)
Phase III ‐ongoing Hoffmann‐La
Roche
114
Aducanumab (BIIB037) Human IgG1 Soluble oligomers and
insoluble fibrils
N‐terminus (residues 2‐9) Phase III ‐ongoing Biogen Idec
115
Crenezumab (MABT5102A) Humanized IgG4 Monomers, oligomers, fibrils Mid domain (residues 13‐24) Phase III ‐ongoing Genentech
118
Abbreviation: AD, Alzheimer's disease.
MOUSSA‐PACHA ET AL.
|
31
fully human IgG1 antibody that targets the fibrillary Aβform and uniquely binds the epitope that involves both, the
N‐terminal (3‐12) and mid‐region (18‐27) residues. Hence, a folded peptide where the mid domain overlaps with
the N‐terminus is preferred.
112
Preclinical studies in transgenic mice confirmed that gantenerumab extensively
reduced Aβdeposits through mediated microglial phagocytosis and blocking the formation of new plaques, without
affecting the systemic Aβlevels.
126
Gantenerumab underwent phase I and II clinical trials in patients with
prodromal AD and was relatively safe, but small group experienced signs of ARIA in a dose and APOE‐ε4 phenotype
dependent manner.
127
Up to date, a phase III randomized trial of gantenerumab in prodromal AD is still ongoing.
128
Another fully human IgG1 mAb is aducanumab (BIIB037, Biogen), that selectively binds the soluble Aβ
aggregates (oligomers) and insoluble fibrils. It targets the residues 2 to 9 at the N‐terminus of Aβpeptide.
123
Preclinical studies in transgenic mice demonstrated the ability of aducanumab analog to cross the BBB, recognize
its Aβtarget and increase the clearance of Aβplaques.
129
Accordingly, aducanumab completed earlier phases of
clinical trials and is currently in phase III studies to measure its efficacy in slowing AD progression and improving
memory loss.
129
Lastly, Crenezumab (MABT5102A, Genentech) is distinctly derived from an IgG4 backbone, thus stimulation of
Fc gamma receptor is diminished. It preferably binds the middle‐regions of various conformations of Aβat the
residues 13 to 24, however, the affinity for capturing oligomers is 10 times higher than for monomers.
130
Moreover, crenezumab and solanezumab recognize the same epitope, although they have a dissimilar binding
pattern. A random coil structure resulted from the binding of crenezumab to Aβbetween residues 21 and 24, while
solanezumab‐Aβ(residues 21‐26) complex produces an alpha‐helical structure.
131
Currently, crenezumab is in
phase III trial for prodromal to patients with mild AD.
132
6
|
FUTURE DIRECTIONS FOR ALZHEIMER'S DISEASE TREATMENT
Alzheimer's disease (AD) is the most devastating neurodegenerative disorder and its pathogeneses are manifested
by many cellular and molecular damage mechanisms, which is attributed to multiple genetic factors. Consequently,
this necessitates the need for multitarget drugs, which might be critical in halting the progression of this complex
disease.
133
Besides, the failure of several clinical trials targeting BACE1 and other targets necessitate the need for
developing novel therapeutic agents with new mechanisms independent of the amyloid hypothesis.
134
Therefore, in
the following sections, important strategies followed to tackle the progression of this devastating disease will be
briefly discussed.
6.1
|
Inhibitors of receptor‐interacting serine/threonine‐protein kinase 1
One of the theories to tackle AD is to prohibit the conversion of microglia to the pathogenic phenotype, which
causes the progression, and development of a series of neurodegenerative disorders including AD.
135
It was
observed that microglia could play a dual role, initially; it helps in clearing out the cellular toxins like the βamyloid
plaques and hyperphosphorylated tau protein. However, when the microglia become chronically inflamed it will
start acting in an opposite manner by expelling large quantities of toxins causing neurons damage and death.
135
Henceforth, the idea was to suppress the inflammation of microglia by inhibiting receptor‐interacting serine/
threonine‐protein kinase 1 (RIPK1). Several studies supported this hypothesis, by showing that the pharmacological
and genetic RIPK1 inhibition results in the reduction of inflammatory mediators and amyloid burden, and improved
memory function (Figure 9). Moreover, these studies approved the role of microglia in promoting the degradation
of Aβin vitro.
136
One of the early compounds discovered for this purpose is necrostatin‐1(31), (Nec‐1; a well‐known RIPIK1
inhibitor (K
D=
3.1 nM)) that has been used in a number of studies to examine RIPK1 function (Figure 10). This
compound was discovered by phenotypic screening for necrotic cell death inhibitors. SAR studies showed that
32
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MOUSSA‐PACHA ET AL.
necrostatin‐1 places the activation segment in the kinase domain of the receptor in the inactive unphosphorylated
confirmation by allosteric inhibition.
137
The compound comprises two main motifs, indoleamine, and thiohydantoin.
Structural alterations in the thiohydantoin group drastically affect the activity. The removal of the thiohydantoin
methyl abolished the inhibitory activity of the compound. On the other hand, converting the thiohydantoin to
hydantoin enhanced the activity.
138
Selectivity of RIPK1 inhibitors is the main concern as the biological effect can
be attributed to binding to other targets since necrostatin‐1 can bind to two other kinase receptors.
139
Moreover,
necrostatin‐1 showed paradoxical finding in terms of the appropriate dosing for administration in disease models of
systemic inflammatory response syndrome (SRIS) which suggests another barrier for its utilization in disease
management.
139
Perhaps these barriers explain the lack of any application of this compound in AD management.
DNL‐747 is another example of RIPK1 inhibitors that reached phase I clinical trials for the treatment of AD,
marking it as the first‐in‐human utilization of RIPK1 inhibitors.
140
Besides the inhibition of microglia inflammation using RIPK1 inhibitors as a strategy to tackle AD, recent work
by Pluvinage et al revealed the presence of B‐cell receptor CD22 on aged microglial cells that promote the
antiphagocytic effect of microglia. Therefore, as an alternative approach, the inhibition of CD22 could switch on the
phagocytic activity of glial cells to clear out the neurotoxins and protein aggregates that are known to be
responsible for AD hallmarks.
141
6.2
|
Inhibitors of glycogen synthase kinase 3β
Glycogen synthase kinase‐3 (GSK‐3) is an enzyme that has been validated as a target for many diseases due to its
vital role and involvement in multiple biological processes including cell division, apoptosis, and insulin production.
GSK‐3 has three isozymes, one of them is glycogen synthase kinase‐3β(GSK‐3β) which is highly abundant in the
brain and is considered one of the driving factors for AD.
142,143
Malfunction of GSK‐3βwas found to be the reason
for the hyperphosphorylation and accumulation of tau protein. In addition, it mediates the production of Aβ, thus
contributing to the development of AD hallmarks.
144
This isozyme is therefore considered one of the attractive
targets on the battle against AD cure and many small molecules were designed to inhibit this protein. These
inhibitors can be grouped into different classes encompassing: irreversible inhibitors, allosteric inhibitors, peptide‐
like inhibitors, metal‐ion inhibitors, adenosine triphosphate (ATP) competitive inhibitors, and non‐ATP competitive
inhibitors.
145
However, inhibiting GSK‐3 features many challenges, both GSK3 isoforms GSK‐3αand GSK‐3βbear
very similar ATP binding sites, therefore it is quite difficult to attain selective inhibitor that can differentiate
between both isoforms. Furthermore, to selectively regulate the activity of GSK‐3β, the inhibitor must interact
specifically with its catalytic triad, Arg96, Arg180, and Lys205. Most of the known GSK‐3βinhibitors have in
common, low molecular weight and flat heterocyclic structure.
146
Many of the GSK‐3βpotent inhibitors were
designed to compete with ATP active site and were derived from pyrrolopyridinone scaffold. Many of these
inhibitors possess IC50s in the nanomolar range and were capable of reducing tau protein phosphorylation,
e,g, pyridyl pyridine derivative, compound 32, Figure 11, with an IC
50
of 4.4 nM.
147
On the other hand, the non‐ATP competitive inhibitors have demonstrated success against GSK‐3β. In this
context, a series of inhibitors was developed having a thiadiazolidinone moiety as the core scaffold. For example,
compound 33 (ie, tideglusib) belongs to this class and is currently in phase II clinical trials for the treatment of mild
to moderate AD.
148,149
These type of ligands are known to act by preventing the indigenous substrate from
accessing the proper orientation of the enzyme binding site.
150
Another class of inhibitors is the irreversible GSK‐3βinhibitors that are characterized by having the α‐halo
methyl group, which is known to bind to Cys199 in the ATP binding site causing an alteration in the active
conformation. In fact, the α‐carbonyl thienyl (compound 34), and its phenyl derivatives (compound 35) showed
potent inhibitory activity and are now in phase II clinical trials.
145
Other important approaches to inhibit GSK‐3βbased on multitarget ligands (MLTs) strategy were considered.
Among others is the dual inhibition of BACE1 and glycogen synthase kinase 3β(GSK‐3β). These motifs contain a
MOUSSA‐PACHA ET AL.
|
33
triazinone scaffold as a suitable ligand to concurrently bind to the aspartic acid residues of BACE1 binding site as
well as the ATP site of GSK‐3β.
151
Perhaps the challenging aspects of GSK‐3 inhibitors design can be circumvented by utilizing other strategies to
block this enzyme. For example, insulin has been extensively examined as one of the suggested novel approaches to
manage AD,
152
where alterations in brain insulin metabolism were considered as one of the underlying causative
factors for this disease.
152
Insulin and GSK‐3 enzyme both regulate glycogen metabolism but in opposite ways.
GSK‐3 is a kinase that keeps glycogen synthase inactive via phosphorylation, whereas insulin tends to activate
glycogen synthetase by dephosphorylation on the same sites.
153
Therefore, in that manner insulin can act to block
GSK‐3 thereby tackling AD. In fact, intranasal insulin is currently in phase III for AD (NCT01767909).
153
In summary, GSK‐3βinhibitors can provide a hopeful approach to tackle AD, since some of the agents in this
class are still in clinical development.
154
Nonetheless, particular concerns raised since these compounds might
induce hypoglycemia and tumorigenesis.
154
Moreover, the need to achieve a proper balance between lipophilicity
to cross BBB and hydrophilicity for oral absorption posed a major concern in their development.
154
Currently,
GSK‐3βnoncompetitive inhibitors appear to be the most promising and safest candidates for clinical use due to
their selectivity and potency.
154
6.3
|
FYN kinase inhibition
Identification of specific signaling pathways responsible for Aβproduction enabled the discovery of promising
interventions that target AD hallmarks.
155
An elegant finding described in 1995 suggested that a soluble rather
than aggregated Aβshowed increased toxicity in neuronal cell cultures.
156
Additional work on the synthesis of Aβ,
identified that the cause of the synaptotoxic material in neuronal cultures was due to Aβoligomers (Aβo), which are
soluble Aβaggregates varying in size from dimers to large molecular weight species.
24,155
The Aβo was found to
interact with the cellular prion protein (PrPC) on the surface of the neuron activating a downstream signaling
pathway converging on the nonreceptor tyrosine kinase Fyn that triggers cellular damage.
24,157
Thus, one of the
proposed therapeutic options that moved beyond the ongoing efforts to remove the soluble assemblies of Aβ(Aβo)
is Fyn inhibition. Fyn is one of the Src family of nonreceptor tyrosine kinases (SFKs), which also includes Src, Lck,
Hck, Blk, Lyn, Fgr, Yes, and Yrk.
158
Pertaining to this hypothesis, transgenic mice models had shown reduced
cognitive functions and enhanced AD phenotype when the function of Fyn increased. However, ablation of Fyn
function has ameliorated AD phenotype.
159
The suggested pathological signaling cascade via SFKs is summarized in
Figure 12, where the extracellular binding domain of Aβo activates the gatekeeper PrPC and Fyn plays a crucial
role in this cascade.
160
Moreover, Fyn has been uniquely linked to the two major pathological hallmarks of AD, because it is not only
activating by Aβvia PrPC, but also it interacts with tau.
155
It has been reported that Fyn is involved in Tau
phosphorylation, which results in synapse damage, behavioral deficits and electroencephalographic deformities in
APP transgenic mice.
161
Thus, many groups attempted to design inhibitors of Fyn protein. Compound 36 (Figure 13), saracatinib
(AZD0530), is one of the orally bioavailable SFK inhibitors with high potency for Src and Fyn, that is currently in an
ongoing phase IIa multicenter study for potential treatment of AD.
159
It inhibits Fyn at the subnanomolar
concentration (IC
50
=8‐10 nM) with excellent pharmacokinetic properties including brain exposure.
159,162
Compound 37, dasatinib (BMS‐354825), is another selective and potent SFK inhibitor with a Fyn IC
50
of 0.2 nM.
162
Furthermore, it has revealed an improvement in the cognition function in transgenic AD mice.
Although, compound 37 might be a promising drug candidate for AD, however, there are no current studies
on patients with AD.
155
It is worth to mention that Fyn is a challenging target with significant homology with other members of SFKs. In
addition, Fyn is implicated in a wide variety of physiological processes that are essential for normal activity, that is,
34
|
MOUSSA‐PACHA ET AL.
the role of Fyn in synaptic function and plasticity. Therefore Fyn inhibition might lead to the development of
unintended adverse effects.
163
6.4
|
Cannabinoid type 2 receptor agonists
Endocannabinoid system (ECS) is an essential network of lipid particles and receptors, which contributes to the
regulatory processes of many physiological functions throughout the human body. The two main endocannabinoid
receptors are the cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors, which belong to the family of
G‐protein‐coupled receptors.
164
CB1 receptors are placed within the central nervous system (CNS) and in
peripheral tissues.
165
They regulate several important brain functions like emotion, memory, cognition, and pain
perception, via the alteration of the excitatory and inhibitory neurotransmission, whereas CB2 receptors are
expressed outside the CNS and can modulate the immune system.
166
Moreover, recent findings have proved the
presence of CB2 receptors in other tissues, that is, CNS.
167
During the last decade, an accumulated body of evidence demonstrated that targeting CB2 receptors might
serve as a promising therapeutic approach for Alzheimer's and other neurodegenerative diseases, as they are
present in dendritic cells, neuronal cells, and microglia.
168
Furthermore, the stimulation of CB2 receptors is
generallyknowntohaveananti‐inflammatory effect or may enhance tissue damage in some conditions.
169
It
should be mentioned that the expression levels of CB2 receptors are dictated by Aβ42 levels and plaque
accumulation, suggesting the stimulation of CB2 receptor expression by these pathogenic events.
170
Thus, the
strong induction of CB2 receptors in the diseased microglia increases the therapeutic benefits, as it would
facilitate selective activation in damaged tissues.
166
Activated microglia generates cytokines, such as TNF‐α,
and inflammatory mediators, along with neurons and astrocytes during neuroinflammation in most of
the neurodegenerative diseases including AD.
171
However, data suggested that Aβaccumulation, and
neuroinflammation and inflammatory mediators release usually coexist, however, the causes are not well
understood.
172
CB2 receptors on the surface of microglia cells inhibit microglia‐mediated neurotoxicity, besides
their indirect role in the regulation of Aβlevels in the brain and the enhancement of Aβclearance.
166
Several
studies have confirmed the anti‐inflammatory effects and the modulation of Aβlevels by CB2 agonists in the in
vivo transgenic mice and in vitro experiments. In this context, the discovery of the selective agonist for CB2,
compound 38 (Figure 14): JWH‐133, with K
i
of 677 nM for CB1 and K
i
of 3.4 nM for CB2,
173
has shown to
improve the cognitive performance, reduce the microglial activation, and response to Aβ, and decrease the
proinflammatory cytokines in APP/PS1 mice.
174
Another CB1/CB2 receptor agonist, compound 39: WIN55,212‐2, showed an increase in the memory function
of Aβ‐induced hippocampal neurodegeneration in adult rats,
175
as well as, a reduction in the release of
proinflammatory cytokines in microglia culture disclosed to the toxic Aβpeptide.
176
Furthermore, compounds 38
and 39, both facilitate the microglial migration, that in turn, induces the phagocytosis of aggregated Aβ.
176
Other studies reported the therapeutic effect of the Δ9‐tetrahydrocannabinol (THC), compound 40,
177
a major
ingredient of Cannabis sativa, in preventing the hallmark characteristics of AD.
178
THC is one of the most potent
CB1 agonists, with an EC
50
less than 50 nM.
179
It enhances Aβdegradation and reduces the intraneuronal Aβ
aggregation. Further research and investigations are still needed to pursue the use of cannabinoids to tackle
dementia in a clinical trial setting. Evidence from preclinical studies suggested that there is a potential for such a
route to provide effective management of AD by targeting the ECS.
180
Therefore, drugs repositioning that is used for other neurodegenerative diseases might give way to surprising
outcome for the management of AD, such as the case of the FDA approved riluzole for amyotrophic lateral sclerosis
(ALS),
181
that is currently under investigation for halting the progression of AD, and the drug is now in phase II
clinical trial entitled: “T2 Protect AD”(NCT03605667). The awaited results of this investigation might offer
additional insight for the potential treatment of AD by utilizing glutamate modulators like riluzole.
181
MOUSSA‐PACHA ET AL.
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35
6.5
|
Tau‐directed potential therapy
One of the AD hallmarks is the neurofibrillary tangles produced as a result of hyperphosphorylated tau protein.
182
Therefore, AD is always correlated with the accumulation of hyperphosphorylated tau proteins that assemble
giving rise to filaments and oligomers which then induce neuronal and glial cells degradation.
182
Consequently, this
accumulation of tau proteins can act as a driver for neurodegenerative conditions known as “tauopathies,”and one
of the AD consequences is due to this phenomena.
183
Therefore, seeking therapeutic alternatives for AD that
target tau proteins has recently captured researchers’interest. In this context, there are many ongoing
investigations targeting the accumulation of tau proteins, among others, is the immunotherapy approach that
indicated promising results reported about the clinical trials progress of many antibodies and vaccines for the
potential treatment of AD.
184,185
In addition, numerous preclinical studies were performed to reduce tau production by targeting tau gene expression
via the antisense oligonucleotide‐based approach. The latter is currently in phase I clinical trials.
186
However, it is worth
mentioning that attempts to reduce tau production bear some consequences as tau proteins are key molecules in
numerous neuronal functions such as microtubules assembly and stability, and axonal transport. Furthermore, it has been
reportedthattaudeletioninmiceresultedinbraininsulin resistance, iron accumulation, and cognitive defects.
187,188
Another strategy in targeting tau accumulation is the anti‐aggregation approach that targets tau proteins phosphorylation
and oligomerization. This strategy utilizes inhibitors of GSK‐3βor activators of phosphatase enzyme that dephosphorylate
tau proteins.
189
Perhaps one of the success stories of the anti‐aggregation strategy is the discovery of compound LMTM
(TRx0237) that advanced to phase III clinical trials.
190
At this junction, the complexity of AD pathogenesis, led scientists to adopt the multitarget‐directed ligands (MTDLs)
approach, in which more than one AD causative path is targeted. In this regard, many examples employing this route were
reported, among others is the design of dual GSK‐3βand acetylcholinesterase inhibitors.
191
In addition, MTDLs might
ameliorate the performance of BACE1 inhibitors and synergize the potential of the AD treatment. Henceforth, many
researchers have dedicated their efforts toward the design of ligands that inhibit BACE1 along with other targets like
GSK‐3β.
192
Another example is dual BACE1/acetylcholinesterase (AChE) inhibitors represented by the rhein‐huprine
hybrid compounds reported by Viayna et al.
193
Despite the fact that the idea of MTDLs is rather captivating and
promising, however, to date none of the MTDLs advanced to clinical trials stages. This might be due to the challenges
encountered when utilizing such a strategy due to the complexity in the design of drugs that modulate the function of
more than one target as well as the complications reported from the in vivo studies.
133
7
|
CONCLUSIONS
Understanding Alzheimer's disease (AD) pathogenesis is rather challenging since the exact biological machinery
that causes AD is not well understood. The current AD treatment options provide only symptomatic management
of the disease and do not reverse the disease progression or the associated neuronal damage.
194
Henceforth,
substantial efforts were made to design and develop new therapeutic agents to halt the progression and manage
the disease. Many of these agents were developed based on the amyloid cascade hypothesis, which offered a
wealth of promising compounds that target the downstream events of Alzheimer disease. Among the most
important proteins is the β‐secretase (BACE1), which is involved in the rate‐limiting step of the β‐amyloid protein
accumulation, therefore, the discovery of BACE1 inhibitors attracted the utmost attention from researchers
worldwide.
13
Synthetic BACE1 inhibitors belong to two major classes, either peptidomimetics or non‐
peptidomimetics. The comparison between these two classes would highly favor the non‐peptidomimetics because
peptidomimetic‐based inhibitors suffered from large size, poor oral bioavailability, short half‐life, weak metabolic
stability, and low BBB penetration.
52
In addition, libraries of inhibitors were isolated from natural sources such as
plants and organisms and showed relatively good BACE1 inhibitory activity.
36
|
MOUSSA‐PACHA ET AL.
Despite the tremendous efforts and the significant expenditure on the development of BACE1 inhibitors that
reached different phases in clinical trials; unfortunately, the latest results reported the failure of many of these
inhibitors, while others are still in ongoing studies and under the investigation with a high possibility to fail as well.
There are several obstacles that must be overcome to allow the design of effective and selective BACE1 inhibitors
to pass advanced clinical trials.
31
Safety concerns have led to the termination of many BACE1 inhibitors in clinical
trials, which have been shown to suffer from off‐target activity, off‐site toxicity or lack of significant physiological
effect in humans, for instance, LY‐2811376 and LY‐2886721 from Eli Lilly, AZD‐3839 from AstraZeneca, and
RG‐7129 from Roche were terminated during clinical trials.
30
Perhaps the failure of these agents could be
attributed to other reasons as AD is a multifactorial abnormality where various hypotheses contributed to its
understanding. Administration of BACE1 inhibitors by patients whom their abnormality was not induced by the
amyloid hypothesis alone will not deliver a clinically efficient therapeutic option for the success of BACE1
inhibitors. Furthermore, the high failure rate of BACE1 inhibitors might be attributed to the nature of BACE1 active
site, which is relatively large and structurally similar to many other aspartyl protease enzymes distributed in
different parts of the human body; therefore, having a small molecule, for example, BACE1 inhibitor, to selectively
occupy such a relatively large active site represents a major challenge.
31
The fact that the structures of all BACE1
inhibitors that were developed so far are flat molecules with high aromatic and SP
2
contents, might explain the
reason behind the lack of selectivity which is responsible for the observed off‐target activities and toxicity effects
of these inhibitors. This necessitates the need for the design of diverse molecular libraries with high 3D‐content to
crosstalk specifically with the high 3D‐content complementary in BACE1. This conclusion is supported by several
examples of successful drug discoveries, which indicated that increasing the SP
3
‐contents of a ligand to better suit
the complementary binding regions of an active site correlates favorably with selectivity and the success rate in
clinical trials.
195-197
Moreover, recent reports illustrated that BACE1 inhibitors caused structural and functional
synaptic impairment that accounts for safety concerns.
106
Additionally, emerging evidence is exposing gender as a
factor to be considered when designing therapeutic option for AD,
198
which requires further investigations to
determine how this element can better shape AD therapy.
104
Since none of the BACE1 inhibitors succeeded so far to offer a clinical benefit that slow or reverse the
progression of AD, this might lead to the conclusion that BACE1 inhibition is a despairing approach to tackle AD.
The failure of many clinical trials, which were based on the amyloid hypothesis, encouraged researchers to consider
new therapeutic agents with mechanisms independent of this hypothesis. Among the new approaches that have
been attempted are the RIPK1, GSK‐3β, Fyn kinase inhibition, and CB2 receptor agonists. Moreover, extensive
efforts were directed toward anti‐Aβimmunotherapy, particularly, the passive immunotherapy that involves
the use of exogenous mAbs. Several engineered mAbs were developed, tested in animals and humans and reached
different stages in clinical trials. Some have failed the clinical trials while others are still in an ongoing study.
112
The continuous search for optimum routes and techniques with significant physiological effects to halt and/or
reverse the progression of AD is underway and the near future may carry hopes for patients suffering from this
mysterious disease. A solution for this complicated disease might exist within the new proposed strategies to unpin
this puzzle since the tremendous efforts spent on developing BACE1 inhibitors did not so far show clinical value.
Lastly, with the fourth industrial revolution is exponentially accelerating toward solving many unmet diseases
facing the mankind using multidimensional approaches, perhaps, the next breakthrough of the 21 century would be
the discovery of a multi‐billion $ drug that ends the mystery of AD.
ACKNOWLEDGEMENTS
This study was supported by generous grants from the Research Funding Department, University of Sharjah, UAE
(15011101007 and 15011101002). We are thankful to Dania Al Ramahi, and Sandi Yaakoub for their help in
gathering some literature data.
MOUSSA‐PACHA ET AL.
|
37
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
ORCID
Hany A. Omar http://orcid.org/0000-0002-4670-8149
Hasan Alniss http://orcid.org/0000-0001-8639-9531
Taleb H. Al‐Tel http://orcid.org/0000-0003-4914-9677
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AUTHOR BIOGRAPHIES
Nour M. Moussa‐Pacha earned a bachelor's degree in pharmacy with highest honors in the academic year
2017‐2018 from University of Sharjah, United Arab Emirates. In October 2018, she started training program in
Dubai Health Authority to get the Professional Licensing in pharmacy.
Shifaa M. Abdin earned a bachelor's degree of pharmacy, in June 2018, from the College of Pharmacy,
University of Sharjah, United Arab Emirates, as 1st achiever (excellent with honor). She is currently enrolled for
M.Sc. degree in Molecular Medicine and Transitional Research at College of Medicine, University of Sharjah,
expected to graduate in June 2020. In addition, she currently works as a research assistant at Sharjah Institute
for Medical Research.
Hany A. Omar Dr. Omar got his Ph.D. in molecular pharmacology and therapeutics at The Ohio State
University, Columbus, Ohio, USA (2010). After post‐doctoral studies at The Ohio State University (2011), he led
cancer cell molecular biology research in different places. He is now an Associate Professor of Molecular
Pharmacology and Therapeutics, University of Sharjah, United Arab Emirates & Beni‐Suef University, Beni‐Suef,
Egypt. He has been a regular reviewer or ad hoc reviewer for several medical journals, different funding agency
and several journal editorial board members and senior editors. Dr. Omar has published over 65 scientific
reports, including many in the most respected professional journals. Current positions: Associate Professor of
Molecular Pharmacology and Therapeutics, Faculty of Pharmacy, Cairo University (BSU Campus), Egypt and
College of Pharmacy, University of Sharjah, UAE. Vice‐Dean and Associate Professor, College of Pharmacy,
University of Sharjah, Sharjah, UAE (2017 to present).
Hasan Alniss received his Ph.D. in Medicinal Chemistry (2011) from the University of Strathclyde—UK. In 2011,
he was appointed Assistant Professor of Medicinal Chemistry at An‐Najah National University (Palestine). In
2013, he was granted the Distinguished Scholar Award and joined the University of Toronto as a Visiting
Professor in the Leslie Dan Faculty of Pharmacy, where he worked with Prof. Robert MacGregor on a project to
characterize the factors that stabilize the G‐quadruplex structures of nucleic acids. In 2015, Dr. Alniss took up
his current position at the University of Sharjah (UAE) as an Assistant Professor of Medicinal Chemistry. In
terms of research, his primary interest is cancer drug discovery and the biophysical characterization of nucleic
acid structures and their complexes with drugs.
Taleb AL‐Tel received his BS in Chemistry and Chemical Technology in 1987, MS in Natural Product Chemistry
in 1990 from the Department of Chemistry, Jordan University and Pennsylvania State University, and
PhD in 1995 from Tuebingen University‐Germany under Professor Wolfgang Voelter followed by an NIH
Postdoctoral Fellowship under the supervision of Professor Scott Sieburth at State University of New York,
Stony Brook, NY. In 2003 he was appointed as a visiting associate professor at Duke Chemistry Department,
North Carolina. Al‐Tel joined Transtech Pharma‐USA, a Drug Discovery and Development Company from 2004
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to 2007 as principal scientist and promoted to a Team Leader. In 2007, he joined the college of
pharmacy‐University of Sharjah in the United Arab Emirates as associate professor of organic medicinal
chemistry then promoted to Professor in 2013. Al‐Tel coauthored over 80 invited lectures, presentations,
keynote Speaker and a coauthor of more than 75 publications in leading journals; inventor on four US‐patents
and patent applications. Al‐Tel received many awards including the German Award for the Exchange of Scholars
(DAAD); Abdel Hameed Shoman Prize for Young Arab Researchers (1999); Fulbright Award (2003/2004). Since
2014, Al‐Tel holds the director position of the Research Institute of Medical and Health Sciences, University of
Sharjah, Sharjah, UAE.
How to cite this article: Moussa‐Pacha NM, Abdin SM, Omar HA, Alniss H, Al‐Tel TH. BACE1 inhibitors:
current status and future directions in treating Alzheimer's disease. Med Res Rev. 2019;1‐46.
https://doi.org/10.1002/med.21622
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