Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 4, 2006
Contents
Proteases as Targets in Medicinal Chemistry
Guest Editor: Dr. Tim F. Tam
Editorial Pp. 287
Matrix Metalloproteinase Inhibitors as Prospective Agents
for the Prevention and Treatment of Cardiovascular and Neoplastic
Diseases Pp. 289-316
Qing-Xiang Amy Sang, Yonghao Jin, Robert G. Newcomer,
Sara C. Monroe, Xuexun Fang, Douglas R. Hurst, Seakwoo Lee,
Qiang Cao, and Martin A. Schwartz
[Abstract]
Structure- and Fragment-Based Approaches to Protease
Inhibition Pp. 317-329
Sherida L. Johnson and Maurizio Pellecchia
[Abstract]
Inhibitors of Cysteine Proteases Pp. 331-353
Radim Vicik, Matthias Busemann, Knut Baumann
and Tanja Schirmeister
[Abstract]
Non-Covalent Cathepsin K Inhibitors for the Treatment
of Osteoporosis Pp. 355-360
Tae-Seong Kim and Andrew S. Tasker
[Abstract]
Characterization and Inhibition of SARS-Coronavirus
Main Protease Pp. 361-376
Po-Huang Liang
[Abstract]
Inhibitors and Modulators of β-
and γ -Secretase
Pp. 377-392
Boris Schmidt, Stefanie Baumann, Hannes A. Braun and Gregor
Larbig
[Abstract]
Targeting Serine Proteases in Asthma Pp.
392-402
Caroline Guay, Michel Laviolette and Guy M. Tremblay
[Abstract]
Abstracts
[Back to top]
Editorial
Protease inhibitors are used to treat and manage a variety
of diseases, and have made its mark in drug development. Angiotensin
converting enzyme (ACE) inhibitors such as captopril, enalapril,
lisinopril, fosinopril, quinapril and ramipril are used to
control blood pressure in hypertensive patients. Human immunodeficiency
virus (HIV) protease inhibitors, exemplified by amprenavir,
indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir
are used in treating acquired immunodeficiency syndrome (AIDS).
Doxycycline hyclate is the first collagenase inhibitor used
for the treatment of periodontal disease. Ximelagatran is
a thrombin inhibitor used in venous thrombosis. Broad spectrum
inhibitors include camostat mesylate and nafamostat, which
help to maintain the pancreatic microcirculation in acute
pancreatitis. Clinical applications of protease inhibitors
were reviewed in 2005 (Fairlie, D.P.; Abbenante, G. Medicinal
Chemistry 2005, 1, 71-104). There is an International
Protease Network (www.protease.net) dedicated to protease
researchers. This reflects the importance of protease inhibitors
as drug candidates for future development.
Proteases play an important role in many pathophysiological
processes. There are four classes of proteases, categorized
by the catalytic residue that effects the hydrolysis of the
substrate’s amide bond, namely the metallo, aspartic,
serine/threonine and cysteine proteases. This special issue
gathers reviews on selected protease targets such as matrix
metalloprotease, SARS-Coronavirus Main protease, cysteine
protease, and secretase inhibition. These reviews emphasize
the latest developments in synthetic inhibitors, the screening
techniques, and the rationale involved in the design of the
inhibitors.
The first monograph by Amy Sang et al. presents an
overview of matrix metalloprotease inhibitors, with particular
emphasis on the use of synthetic inhibitors as prospective
agents for the prevention and treatment of cardiovascular
and neoplastic diseases. Maurizio Pellechia et al.
provide an overview of the use of structure- and fragment-based
design guided by X-ray crystallography, NMR spectroscopy,
computational and/or extended tethering approaches for the
identification of potential non-peptidic agents as cysteine
and metalloprotease inhibitors.
Tanya Schirmeister et al. describe the design of
cysteine protease inhibitors with an electrophilic moiety
that can covalently bind to the cysteine residue of the active
site of the target protease. Examples of such inhibitors are
aziridine derivatives and analogues of the diuretic drug,
ethacrynic acid. Selective inhibition of cathepsin K has emerged
as a potential new therapy for the treatment of osteoporosis.
Tae-Seong Kim et al. report the research and development
of a series of non-peptidic cathepsin K inhibitors as an alternative
to the use of bisphosphonates and anti-RANK ligand therapies.
Severe acute respiratory syndrome (SARS) is an emerging infectious
disease caused by a novel human coronavirus (CoV). A 3C-like
cysteine protease is essential for the life cycle of SARS-CoV.
Po-Huang Liang reviews the characterization of SARS-Coronavirus
Main protease and various lead inhibitors. This special issue
then shifts to the research and development of β-
and γ-secretase
inhibitors. These two aspartyl proteases cleave amyloid precursor
protein to yield amyloid β.
Boris Schmidt et al. describe the selective inhibition
of both aspartyl proteases, their peptidic and non-peptidic
lead inhibitors, and the metabolism of amyloid precursor protein
as a potential cause of Alzheimer’s disease. Guy Tremblay
et al. discuss the importance of tryptase, and chymase
in asthma, and the strategies used to inhibit their detrimental
action.
I would like to thank the authors for their excellent and
timely reviews in their respective fields of expertise, and
the reviewers for their suggestions and helpful discussions.
This special issue is intended to provide the reader with
many of the useful concepts and techniques employed in the
medicinal chemistry of protease inhibitors. It is not exhaustive,
but it provides a concise update for those already familiar
with protease research, and an initial reference resource
for those wishing to obtain more detailed information on the
topic.
Dr. Tim F. Tam
Medicinal Chemistry Department
ApoPharma Inc.
400 Ormont Drive
Toronto, Ontario
Canada M9L 1N9
E-mail: ttam@apotex.com
[Back to top]
Matrix Metalloproteinase Inhibitors as Prospective
Agents for the Prevention and Treatment of Cardiovascular
and Neoplastic Diseases
Qing-Xiang Amy Sang, Yonghao Jin, Robert G. Newcomer,
Sara C. Monroe, Xuexun Fang, Douglas R. Hurst, Seakwoo Lee,
Qiang Cao, and Martin A. Schwartz
Acting on a broad spectrum of extracellular, intracellular,
and membrane-associated substrates, the matrix metalloproteinases
(MMPs) are critical to the biological processes of organisms;
when aberrantly expressed, many pathological conditions may
be born or exacerbated. The prospect of MMP inhibition for
therapeutic benefit in cancer, cardiovascular disease, and
stroke is reviewed here. MMP inhibitor (MMPI) development
constitutes an important branch of research in both academic
and industrial settings and advances our knowledge on the
structure-function relationship of MMPs. Targeting MMPs in
disease treatment is complicated by the fact that MMPs are
indispensable for normal development and physiology and by
their multi-functionality, possible functional redundancy
or contradiction, and context-dependent expression and activity.
This complexity was revealed by previous efforts to inhibit
MMP activity in the treatment of cancer patients that yielded
unsatisfactory results. This review focuses on MMPI development
since the late 90s, in terms of natural products and their
derivatives, and synthetic compounds of low molecular mass
incorporating specific zinc-binding groups (ZBGs). A few polyphenols
and flavonoids that exhibit MMPI activities may have chemopreventive
and neuro- and cardiovascular-protective effects. A new generation
of potent and selective MMPIs with novel ZBGs and inhibition
mechanisms have been designed, synthesized, and tested. Although
only one collagenase inhibitor (Periostat, doxycycline hyclate)
has been approved by the Food and Drug Administration as a
drug for the treatment of periodontal disease, new hope is
emerging in the form of natural and synthetic MMPIs for the
prevention and treatment of stroke, cardiovascular disease,
cancer, and other medical conditions.
[Back to top]
Structure- and Fragment-Based Approaches to Protease
Inhibition
Sherida L. Johnson and Maurizio Pellecchia
Proteases are essential enzymes which regulate
physiological processes such as inflammation, infection, fertilization,
allergic reactions, cell growth and death, blood clotting,
tumor growth and bone remodeling. The protease family consists
of six major classes of enzymes which are aspartic-, serine-,
cysteine-, threonine-, glutamic-, and metallo-proteases, all
which are implicated in disease propagation. Therefore, protease
inhibitors have been of great interest as possible targets
for the development of novel therapies. Although, many protease
inhibitors have followed a structural design based on either
a peptidic or peptidomimetic backbone, other chemical scaffolds
have recently emerged. Utilizing structure- and fragment-based
design guided by X-ray crystallography, NMR spectroscopy,
computational and/or extended tethering approaches, potential
non-peptidic therapeutic agents could be identified. In this
review, we will report on the recent developments of nonpeptidic
cysteine- and metallo- protease inhibitors, focusing on their
design by using such strategies.
[Back to top]
Inhibitors of Cysteine Proteases
Radim Vicik, Matthias Busemann, Knut Baumann
and Tanja Schirmeister
The roles of cysteine proteases (CP) as protein
degrading and protein processing enzymes both in physiological
and pathological processes of mammals are well known. Furthermore,
the key roles of CP`s in the life cycles of infectious agents
like protozoa and viruses turn them into new important targets
for anti-infective drugs. Thus, the effective inhibition of
pathologically relevant cysteine proteases has raised increasing
interest in drug development.
One strategy to create CP inhibitors is the use of electrophilic
moieties, which covalently bind to the cysteine residue of
the active site of the target protease. In a previous approach
we have selected the aziridine-2,3-dicarboxylic acid as weak
electrophilic inhibitor fragment. In order to achieve effective
enzyme inhibition this electrophile was incorporated into
peptidic or peptidomimetic sequences addressing the substrate
binding sites of the protease. High selectivity could be obtained
with compounds, which bind into both the primed and non-primed
substrate binding pockets.
In a second approach the α,β-unsaturated
ketone of the well-known diuretic drug ethacrynic acid was
found to be another appropriate electrophilic moiety. Derivatives
thereof turned out to be new non-peptidic CP inhibitors. Results
of inhibition assays obtained with these two inhibitor series
on various proteases of human, protozoan, and viral origin,
theoretical studies to investigate binding modes and inhibition
mechanisms, and structure-activity relationships are presented.
Furthermore, the results of in vitro assays on respective
pathogens as well as the results of first toxicity studies
are summarized.
[Back to top]
Non-Covalent Cathepsin K Inhibitors for the Treatment
of Osteoporosis
Tae-Seong Kim and Andrew S. Tasker
Cathepsin K is a cysteine protease that
plays an important role in the pathological process of bone
resorption. Selective cathepsin K inhibitors may thus provide
great potential in the treatment of osteoporosis. Pharmaceutical
interest in this area is highlighted by the rising number
of publications and patent applications. Most recently, the
interim results of three clinical trials conducted by Novartis,
GlaxoSmithKline, and Merck have strengthened the validation
of the target for the therapeutic intervention of osteoporosis.
Here we report a series of Cbz-leucyl-(4-piperidinylphenyl)aminoethyl
amides based on dipeptidyl anilines for cathepsin K inhibition.
These new non-covalent inhibitors exhibit single digit nM
inhibition of the cathepsin family. Molecular modeling studies
on the interactions responsible for the potency of these inhibitors
for cathepsin K will be also discussed.
[Back to top]
Characterization and Inhibition of SARS-Coronavirus
Main Protease
Po-Huang Liang
Severe acute respiratory syndrome (SARS) is an emerging infectious
disease caused by a novel human coronavirus (CoV). During
the 2003 epidemic, the disease rapidly spread from its origin
in southern China to other countries and affected almost 8000
patients, which resulted in about 800 fatalities. A chymotrypsin-like
cysteine protease named 3C-like protease (3CLpro)
is essential for the life cycle of the SARS-CoV. This main
protease is responsible for maturation of functional proteins
and represents a key anti-viral target. HPLC and fluorescence-based
assays have been used to characterize the protease and to
determine the potency of the inhibitors. The fluorogenic method
monitoring the increase of fluorescence from the cleavage
of a peptide substrate containing an Edans-Dabcyl fluorescence
quenching pair at two ends has enabled the use of high throughput
screening to speed up the drug discovery process. Several
groups of inhibitors have been identified through high throughput
screening and rational drug design approaches. Thus, α,β-unsaturated
peptidomimetics, anilides, metal-conjugated compounds, boronic
acids, quinolinecarboxylate derivatives, thiophenecarboxylates,
phthalhydrazide-substituted ketoglutamine analogues, isatin
and natural products have been identified as potent inhibitors
of the SARS-CoV main protease. The different classes of inhibitors
reported in these studies are summarized in this review. Some
of these inhibitors could be developed into potential drug
candidates, which may provide a solution to combat possible
reoccurrence of the SARS and other life-threatening viruses
with 3CL proteases.
[Back to top]
Inhibitors and Modulators of β-
and γ -Secretase
Boris Schmidt, Stefanie Baumann, Hannes A. Braun and Gregor
Larbig
Most gene mutations associated with Alzheimer’s disease
point to the metabolism of amyloid precursor protein as potential
cause. The β-
and γ-secretases
are two executioners of amyloid precursor protein processing
resulting in amyloid β.
Significant progress has been made in the selective inhibition
of both proteases, regardless of structural information for
γ-secretase.
Several peptidic and non-peptidic leads were identified and
first drug candidates are in clinical trials. This review
focuses on the developments since 2003.
[Back to top]
Targeting Serine Proteases in Asthma
Caroline Guay, Michel Laviolette and Guy M. Tremblay
Leukocytes and lung structural cells contribute to the
pathophysiology of asthma through the production of numerous
mediators including serine proteases. Such proteases include
mast cell tryptase and chymase; neutrophil elastase, cathepsin
G and myeloblastin (proteinase 3); bronchial epithelial cell-derived
transmembrane protease, serine 11D (human airway trypsin-like
protease); cytotoxic T lymphocyte- and natural killer cell-derived
granzyme B; and, eosinophil serine protease 1 (testisin).
Considerable effort to develop potent and selective inhibitors,
mostly non-peptidic, especially targeting tryptase and chymase
have been made in the last few years. This review presents
promising inhibitors, currently in the research and development
pipeline. Some endogenous inhibitors and other compounds purified
from non-human species are also discussed.
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