Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 8, Number 1, 2008
Contents
Gamma-Secretase Inhibitors and Modulators
as a Therapeutic Approach to Alzheimer’s disease
Guest Editor: Bruno P. Imbimbo
Editorial Pp. 1
γ-Secretase:
Structure, Function, and Modulation for Alzheimer’s
Disease Pp. 2-8
Michael S. Wolfe
[Abstract]
Activity of γ-Secretase
on Substrates Other than APP Pp. 9-16
M.D. Alberto Lleó
[Abstract]
Recent Progress in the Medicinal Chemistry of γ
Secretase Inhibitors Pp.17-33
Richard E. Olson and Charles F. Albright
[Abstract]
γ-Secretase
Modulation and its Promise for Alzheimer's disease: a Rationale
for Drug Discovery Pp. 34-37
Dirk Beher
[Abstract]
γ-Secretase
Modulation and its Promise for Alzheimer’s Disease:
a Medicinal Chemistry Perspective Pp. 38-46
Ilaria Peretto and Elena La Porta
[Abstract]
Possible Mechanisms of Action of NSAIDs and Related
Compounds that Modulate γ-Secretase
Cleavage Pp. 47-53
Thomas Kukar and Todd E. Golde
[Abstract]
Therapeutic Potential of γ-Secretase
Inhibitors and Modulators Pp. 54-61
Bruno P. Imbimbo
[Abstract]
Molecule
of Month Pp. 62
Abstracts
[Back to top]
Editorial
Alzheimer's disease (AD) is the most common cause of dementia.
According to the so called “amyloid hypothesis”,
the oligomeric forms of a 40-42 aminoacid peptide known as
β-amyloid
(Aβ),
is the main cause of neuronal death in AD. Aβ
is the metabolite of a large transmembrane protein called
amyloid precursor protein (APP). The last metabolic step that
generates Aβ
involves the enzymatic intramembrane cleavage of APP by a
high-molecular weight complex called γ-secretase.
γ-Secretase
is formed by at least four proteins: presenilin (PS), nicastrin,
anterior pharynx (Aph-1) and presenilin enhancer 2 (Pen-2).
Presenilins are of exceptional pathophysiological importance
since more than 150 autosomal dominant point mutations are
known in these proteins, all of which cause aggressive early-onset
AD. These mutations result in increased production of Aβ42,
the highly self-aggregating and neurotoxic form of Aβ.
Thus, inhibition or modulation of γ-secretase
appears to be a logical strategy to decrease Aβ
accumulation in AD patients.
To fully explore recent advances in the γ-secretase
field, Current Topics in Medicinal Chemistry has
devoted this entire issue to a review of the structure and
function of the γ-secretase
complex and summarizes SARs of the main peptidic and non-peptidic
inhibitors of the enzyme. In addition, allosteric modulators
of γ-secretase
are described since they may represent a safer approach to
inhibit Aβ
secretion in AD patients. Finally, I have reviewed the γ-secretase
inhibitors and modulators that have been selected for development
and describe data obtained so far from clinical trials. With
a number of companies conducting clinical trials with γ-secretase
inhibitors and modulators, it should become clear in the near
future whether this attractive target for decreasing Aβ
can lead to effective and safe drugs for AD.
I would like to express my gratitude to all the Authors for
their clear and comprehensive contributions to this special
issue of Current Topics in Medicinal Chemistry. Our
hope is that this issue will be an informative contribution
to the field and will represent a key reference work for those
involved in the discovery of γ-secretase
inhibitors and modulators.
Bruno P. Imbimbo
Research & Development Department,
Chiesi Farmaceutici,
Parma,
Italy
[Back to top]
γ-Secretase: Structure, Function, and Modulation
for Alzheimer’s Disease
Michael S. Wolfe
γ-Secretase
proteolyzes a variety of membrane-associated fragments derived
from type I integral membrane proteins, including the amyloid
β-protein
precursor, involved in Alzheimer’s disease, and the
Notch receptor, critical for cellular differentiation. This
protease is composed of four integral membrane proteins: presenilin,
nicastrin, Aph-1 and Pen-2. Assembly of these four components
leads to presenilin autoproteolysis into two subunits, each
of which contributes one aspartate to the active site of an
aspartyl protease. The protease contains an initial docking
site for substrate, where it binds prior to passing between
the two presenilin subunits to the internal water-containing
active site. The extracellular region of nicastrin also interacts
with the N-terminus of the substrate as an essential step
in substrate recognition and processing. Modulation of APP
processing without interfering with Notch signaling is an
important therapeutic goal, and allosteric sites on the protease
allow such selective modulation. A better structural and mechanistic
understanding of γ-secretase
should ultimately allow structure-based design of more potent
and selective modulators.
[Back to top]
Activity of γ-Secretase
on Substrates Other than APP
M.D. Alberto Lleó
γ-secretase
is an intramembranous protein complex that cleaves many type-I
membrane proteins, including the Notch receptor and the β-amyloid
precursor protein (APP). Interest in γ-secretase
comes, in part, from the fact that this multiprotein complex
is responsible for the cleavage of APP that generates the
amyloid-β
peptide (Aβ),
one of the primary components of amyloid plaques in Alzheimer’s
disease (AD). Over the last years, molecular identification
of the complex has shown that γ-secretase
is an aspartyl protease composed of four different members
that are essential for the enzymatic activity: presenilin
1, aph1, pen-2 and nicastrin. In recent years, an increasing
number of type-I membrane proteins have been shown to be cleaved
by γ-secretase.
How the enzyme cleaves such a set of substrates with diverse
functions and subcellular localizations is not well understood.
In overexpression assays, the γ-secretase
cleavage of some substrates releases intracellular domains
with signaling properties. On the other hand, the loose specificity
required for intramembrane cleavage has raised the possibility
of γ-secretase
as the membrane proteasome. The impact of γ-secretase
on other substrates has clear implications for the development
of new therapies for AD, and in particular for the search
of γ-secretase
inhibitors or modulators. Interference with the cleavage of
some of the γ-secretase
substrates has been shown to be associated with serious adverse
effects in animal models. The understanding of the mechanism
by which γ-secretase
recognizes and cleaves all these proteins is of great importance
to clarify the function of γ-secretase
and its role as a therapeutic target in AD, and possibly in
other diseases in which γ-secretase
is involved.
[Back to top]
Recent Progress in the Medicinal Chemistry of γ
Secretase Inhibitors
Richard E. Olson and Charles F. Albright
Aβ
is implicated in the initiation and progression of Alzheimer’s
disease (AD) by the phenotypic analysis of mutations in three
human genes that lead to inherited, early forms of AD and
data from preclinical studies. Based on this evidence, γ-secretase
inhibitors are being actively pursued as potential AD therapeutics
to reduce Aβ
formation. This manuscript reviews recent progress in the
medicinal chemistry of three major classes of γ-secretase
inhibitors: peptide isosteres, azepines, and sulfonamides.
Peptide isosteres have been useful for demonstrating that
presenilin is the catalytic subunit of γ-secretase
and probing the active site. The peptidic nature of these
inhibitors has, however, interfered with their utility for
in vivo studies. Instead, the pharmaceutical industry
has focused on optimizing azepines and sulfonamides. Both
azepines and sulfonamides bind to a common, allosteric site
on presenilin that differs from the active site identified
by the peptide isosteres. Significant progress in the optimization
of both azepines and sulfonamides has led to compounds that
inhibit brain Aβ
synthesis in preclinical models and has culminated in the
identification of γ-secretase
inhibitors, including LY-450139 and MK-0752, for human trials.
[Back
to top]
γ-Secretase Modulation and its Promise for Alzheimer's
disease: a Rationale for Drug Discovery
Dirk Beher
The genetics of Alzheimer’s disease (AD) implies
that restoring non-pathological levels or ratios of different
amyloid-β
(Aβ)
peptide species in the brain could prevent the onset or delay
the progression of this neurodegenerative disease. In particular,
a selective reduction of the longer Aβ(1
42) peptide which is widely believed to be causative of AD
is currently seen as an attractive approach for a disease-modifying
therapy. Based on the knowledge that Aβ(1-42)
and various shorter Aβ
peptides are generated by the same γ
secretase enzyme, the concept of allosteric modulation of
the cleavage specificity of this aspartic protease has been
introduced to the field of protease drug discovery and fuelled
novel medicinal chemistry efforts. γ-Secretase
modulation holds the promise that chemical entities can be
synthesized which restore non-pathological enzyme activity
by shifting the actual substrate cleavage towards the generation
of shorter Aβ
peptides. It can be assumed that this approach has gained
considerable attraction for pharmaceutical drug discovery
since the development of non-selective protease inhibitors
for γ-secretase
has been proven to be difficult due to inherent mechanism-based
liabilities.
[Back
to top]
γ-Secretase Modulation and its Promise for Alzheimer’s
Disease: a Medicinal Chemistry Perspective
Ilaria Peretto and Elena La Porta
γ-Secretase
modulation holds the promise for the development of a disease-modifying
therapy for Alzheimer’s disease (AD). This novel concept
of manipulating the cleavage specificity of the γ
secretase enzyme by pharmacological means implies that steady
state levels of the potentially disease-causing amyloid-β(1-42)
peptide can be lowered without the undesired side effects
associated with full inhibition of this aspartyl-type protease.
Following on from the initial discovery that certain non-steroidal
anti-inflammatory drugs (NSAIDs) exhibit properties characteristic
of γ
secretase modulators, this class of compounds has been extensively
studied and exploited, leading to the discovery of NSAIDs
derivatives endowed with improved potency for the reduction
of amyloid-β(1-42)
peptide production. In addition, a very limited number of
non-NSAID derived γ
secretase modulators has also been recently claimed in the
patent literature, suggesting that only a restricted number
of pharmacophores might be involved in the modulation of γ-secretase.
[Back to top]
Possible Mechanisms of Action of NSAIDs and Related Compounds
that Modulate γ-Secretase
Cleavage
Thomas Kukar and Todd E. Golde
Genetic and biochemical evidence continues to implicate
the production and accumulation of the Aβ42
peptide as the causative factor in Alzheimer’s disease
(AD). Thus, a variety of strategies have been developed to
decrease the production and/or aggregation of this peptide,
which may be clinically useful for the treatment of this devastating
disorder. Recently, the discovery that some non-steroidal
anti-inflammatory drugs (NSAIDs) appear to selectively decrease
the production of Aβ42
has opened a novel therapeutic avenue for AD treatment that
may circumvent potential toxicity associated with long-term
global inhibition of γ-secretase
activity. One drug from this class of compounds, R-flurbiprofen,
has advanced to phase 3 clinical trials and may soon provide
insight into the viability of this strategy for the prevention
or treatment of AD. Delineating the target and mechanism of
these compounds is essential for developing new agents with
increased potency and optimized pharmacologic properties.
The evidence indicating that these chemicals modulate the
production of Aβ
peptides by directly interacting with the γ-secretase
complex is summarized.
[Back to top]
Therapeutic Potential of γ-Secretase
Inhibitors and Modulators
Bruno P. Imbimbo
According to the β-amyloid
(Aβ)
hypothesis, compounds that inhibit γ-secretase,
the pivotal enzyme that generates Aβ,
are potential therapeutics for Alzheimer’s disease (AD).
Studies in both transgenic and non-transgenic animal models
of AD have indicated that γ-secretase
inhibitors, administered by the oral route, are able to lower
brain Aβ
concentrations. However, scanty data are available on the
effects of these compounds on brain Aβ
deposition after prolonged administration. Behavioral studies
are also scarce with only one study indicating positive cognitive
effects of a peptidomimetic compound (DAPT). γ-Secretase
inhibitors may cause abnormalities in the gastrointestinal
tract, thymus and spleen in rodents. These toxic effects are
likely due to inhibition of Notch cleavage, a transmembrane
receptor involved in regulating cell-fate decisions. Interestingly,
some non-steroidal anti-inflammatory drugs (NSAIDs) and other
small organic molecules have been found to modulate γ-secretase
and to selectively reduce β-amyloid1-42
(Aβ42)
levels without affecting Notch cleavage. Long-term histopathological
and behavioral animal studies are available with these NSAIDs
(mainly ibuprofen) but it is unclear if the observed in vivo
effects on Aβ
brain pathology and learning depend on their activity on γ-secretase
or on other biological targets. The first published clinical
studies in healthy subjects and in AD patients with a γ-secretase
inhibitor, LY-450139, confirmed the dose-dependent inhibition
of plasma Aβ
but evidenced a later rebound in Aβ
plasma levels and absence of a significant effect on cerebrospinal
fluid Aβ
concentrations. Some observed gastrointestinal adverse events
have raised concerns. Clinical studies with other potent γ-secretase
inhibitors will tell us if these pharmacodynamic and tolerability
profiles observed in humans are typical of the pharmacological
class or are compound-specific. Given the uncertain Aβ
reduction target and the potential for mechanism-based toxicity,
it has been suggested that biomarkers for efficacy (cerebrospinal
fluid Aβ42
levels) and toxicity (plasma adipsin levels) would be helpful
in initial clinical trials with γ-secretase
inhibitors. A large ongoing Phase 3 study with (R)-flurbiprofen,
a claimed selective Aβ42
lowering agent, will tell us if allosteric modulation of γ-secretase
is clinically effective.
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