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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 12, Number 25, 2005
Contents
Tumour Necrosis Factor Alpha Converting Enzyme
Guest Editor: David Fairlie
Editorial Pp. 2923-2924
Therapeutic Targets in Inflammatory Disease Pp.
2925-2929
David A. Hume and David P. Fairlie
[Abstract]
Drugs To Treat Inflammation: A Historical Introduction
Pp. 2931-2942
Michael W. Whitehouse
[Abstract]
Antibody Treatments of Inflammatory Arthritis
Pp. 2943-2946
Matthew A. Brown
[Abstract]
Anti-Inflammatory Immunotherapy for Multiple Sclerosis/Experimental
Autoimmune Encephalomyelitis (EAE) Disease Pp. 2947-2962
Jagat R. Kanwar
[Abstract]
Inhibitors of TACE and Caspase-1 As Anti-inflammatory
Drugs Pp. 2963-2977
Giang T. Le and Giovanni Abbenante
[Abstract]
MAP Kinase p38 Inhibitors: Clinical Results and an
Intimate Look at Their Interactions with p38α
Protein Pp. 2979-2994
Matthew R. Lee and Celia Dominguez
[Abstract]
PPARs in Disease: Control Mechanisms of Inflammation
Pp. 2995-3009
Radina Kostadinova, Walter Wahli and Liliane
Michalik
[Abstract]
Inhibitors of Secretory Phospholipase A2
Group IIA Pp. 3011-3026
Robert C. Reid
[Abstract]
Nonpeptide Ligands That Target Peptide-Activated GPCRs
In Inflammation Pp. 3027-3042
Jade S. Blakeney and David P. Fairlie
[Abstract]
Abstracts
[Back to top]
Editorial
To the medicinal chemist uninitiated in the field, inflammation
can be an intimidating research area to tackle. There is a
bewildering array of prospective targets for antiinflammatory
drugs, with countless enzyme inhibitors, receptor antagonists,
and other experimental antiinflammatory agents already known.
Despite many decades of research, the biology that underpins
inflammation, the immune response to infection and injury,
and the mechanistic basis for therapies, is still in need
of considerable unravelling. Fortunately, the genomic/proteomic
revolution that has been taking place is providing new tools
and an unprecedented volume of new information that promises
to dramatically improve our understanding of inflammatory
networks, and how best to intervene in them for maximum therapeutic
gain.
In this issue, Hume et al. present a short commentary
on inflammation and inflammatory targets of relevance to other
articles that follow. They describe some factors that limit
either the effectiveness of inflammatory targets or the rate
of discovery of antiinflammatory drugs, and comment briefly
on future prospects for targeting proteins that mediate inflammatory
responses. Whitehouse completes the introduction by overviewing
the historical development of antiinflammatory therapies,
focussing on some of the problems encountered in drug development
during the past century and some important lessons that were
learned along the way.
Brown describes antibody treatments for inflammatory arthritis
(e.g. rheumatoid arthritis, ankylosing spondylitis, psoriatic
arthritis), including some of their limitations as well as
opportunities for developing new antibody based anti-inflammatory
therapies. Kanwar also overviews antibody therapies, but for
the treatment of multiple sclerosis, including properties
of antibodies in animal models of experimental autoimmune
encephalomyelitis (EAE).
Numerous proteolytic enzymes are implicated in the pathogenesis
of chronic inflammatory diseases. Abbenante and Le describe
the current status of development of small nonpeptidic inhibitors
of two such enzymes, the metalloprotease TACE (Tumour necrosis
factor Alpha Converting Enzyme) and the cysteine protease
Caspase-1 (formerly ICE, Interleukin Converting Enzyme). Such
enzymes are responsible for producing the crucial proinflammatory
mediators TNFα
and IL1β,
and selective inhibitors of such enzymes are expected to be
effective antinflammatory drugs that should also be much cheaper
and more accessible to the public than currently used antibody
based therapies.
Lee and Dominguez describe some clinical results for inhibitors
of the serine/threonine kinase known as mitogen-activated
protein kinase p38 (MAP kinase p38) and especially focus on
inhibitor interactions with the best studied isoform, p38α
protein. Kostadinova et al. overview peroxisome proliferator-activated
receptors (PPARs) and their inhibitors in inflammation and
disease. Reid surveys structures of inhibitors of secreted
phospholipase A2 (group IIa) and discusses their potential
roles as antiinflammatory drugs. Blakeney et al.
survey some 30 GPCRs implicated in inflammation and describe
structures and properties of some 60 agonists/antagonists
with antiinflammatory activity.
This issue represents only a tiny fraction of the already
known number of inflammatory drug targets but offers a reasonable
platform for benchmarking future developments in antiinflammatory
drugs both for these targets and others.
David Fairlie
Guest Editor
Centre for Drug Design and Development,
Institute for Molecular Bioscience,
University of Queensland, Brisbane,
Qld 4072, Australia
Fax: +61-7-33462990
E-mail: d.fairlie@imb.uq.edu.au
[Back to top]
Therapeutic Targets in Inflammatory Disease
David A. Hume and David P. Fairlie
This commentary is an introduction to a special issue on
“Latest Developments in the Treatment of Inflammation”.
It outlines some key events in the inflammatory response to
infection or injury and describes some of the important drug
targets of relevance to the succeeding articles, which survey
inhibitors of these targets as prospective or current antiinflammatory
drugs. It also highlights important limitations in the validation
of inflammatory drug targets, and in the rate of discovery
and development of new antiinflammatory drugs.
[Back to top]
Drugs To Treat Inflammation: A Historical Introduction
Michael W. Whitehouse
Drugs to treat inflammation are discussed under the following
headings: (1) random discoveries covering copper, salicylates,
heterocyclic diones, ACTH, adrenal steroids and disease-modifying
agents (DMARDs); these include Au(I)-thiolates, chloroquine,
and hydroxychloroquine, minocycline, cyclosporin, salazopyrine,
D-penicillamine and methotrexate; (2) programmed NSAID developments
covering salicylates and fenamates, arylalkanoates, diones,
non-acidic NSAIDs, clozic, lobenzarit and coxibs; (3) synthetic
glucocorticosteroids; and (4) ‘Biologicals’ for
neutralising pro-inflammatory cytokines. Clinical problems
are highlighted, particularly unacceptable side-effects affecting
the GI tract, skin, liver, etc. that caused many drugs to
be withdrawn. Drug combinations may overcome some of these
problems. The bibliography has selected reviews and monographs
covering 50 years of publications.
[Back to top]
Antibody Treatments of Inflammatory Arthritis
Matthew A. Brown
Inflammatory arthropathies such as rheumatoid arthritis,
ankylosing spondylitis, and psoriatic arthritis are extremely
common in the community, with a prevalence of up to 5%, and
they cause substantial morbidity. The development of anti-TNF
agents for use initially in rheumatoid arthritis, and subsequently
more broadly in inflammatory arthritis, represents the biggest
advance in management of these conditions since the introduction
of corticosteroid agents, and is a major vindication of public
funded arthritis research. However, there are limitations
of even these highly effective agents. A significant minority
of patients with inflammatory arthritis do not respond to
these anti-TNF agents, they are associated with substantial
risk of toxicity, require parenteral administration, and are
extremely expensive. New antibody treatments in development
can be divided into anti-cytokine agents, cell-targeted therapies,
co-stimulation inhibitors, and treatments aimed at preventing
joint erosion consequent on inflammation. This review discusses
the state of the art in the development of these agents for
management of this common group of diseases.
[Back to top]
Anti-Inflammatory Immunotherapy for Multiple Sclerosis/Experimental
Autoimmune Encephalomyelitis (EAE) Disease
Jagat R. Kanwar
Multiple sclerosis (MS) and its animal model, experimental
autoimmune encephalomyelitis (EAE), are inflammatory diseases
of the central nervous system (CNS) characterized by localized
areas with demyelination. Disease is believed to be an autoimmune
disorder mediated by activated immune cells such as T- and
B-lymphocytes and macrophages/microglia. Lymphocytes are primed
in the peripheral tissues by antigens, and clonally expanded
cells infiltrate the CNS. They produce large amounts of inflammatory
cytokines, nitric oxide (NO) that lead to demyelination and
axonal degeneration. Although several studies have shown that
oligodendrocytes (OLGs), the myelin-forming glial cells in
the CNS, are sensitive to cell death stimuli, such as cytotoxic
cytokines, anti-myelin antibodies, NO, and oxidative stress,
in vitro, the mechanisms underlying injury to the
OLGs in MS/EAE remain unclear. The central role of glutamate
receptors in mediating excitotoxic neuronal death in stroke,
epilepsy, trauma and MS has been well established. Glutamate
is the major excitatory amino acid transmitter within the
CNS and it's signaling is mediated by a number of postsynaptic
ionotropic and metabotropic receptors. Inflammation can be
blocked with anti-cell adhesion molecules MAb, simultaneously
protected oligodendrocytes and neurons against glutamate-mediated
damage with the AMPA/kainate antagonist NBQX, and the NMDA
receptor antagonist GPE, could thus be effective therapies
for multiple sclerosis.
[Back to top]
Inhibitors of TACE and Caspase-1 As Anti-inflammatory
Drugs
Giang T. Le and Giovanni Abbenante
TNF-α
neutralising agents such as Infliximab (Remicade®), Etanercept
(Enbrel®) and the IL-1 receptor antagonist Anakinra (Kineret®),
are currently used clinically for the treatment of many inflammatory
diseases such as Crohn’s disease, rheumatoid arthritis,
ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic
arthritis and psoriasis. These protein preparations are expensive
to manufacture and administer, need to be injected and can
cause allergic reactions. An alternative approach to lowering
the levels of TNF-α
and IL-1β & in inflammatory disease, is to inhibit
the enzymes that generate these cytokines using cheaper small
molecules. This paper is a broad overview of the progress
that has been achieved so far, with respect to small molecule
inhibitor design and pharmacological studies (in animals and
humans), for the metalloprotease Tumour Necrosis Factor-α
Converting Enzyme (TACE) and the cysteine protease Caspase-1
(Interleukin-1β Converting Enzyme, ICE). Inhibitors of
these two enzymes are currently considered to be good therapeutic
targets that have the potential to provide relatively inexpensive
and orally bioavailable anti-inflammatory agents in the future.
[Back to top]
MAP Kinase p38 Inhibitors: Clinical Results and an
Intimate Look at Their Interactions with p38α
Protein
Matthew R. Lee and Celia Domingue
Mitogen-activated protein kinase p38 is a serine/threonine
kinase originally isolated from lipopolysaccharide (LPS) stimulated
monocytes. There are four isoforms p38α,
p38β, p38g, and p38δ.
The most thoroughly studied isoform is p38α,
whose activation has been observed in many hematopoietic and
non-hematopoietic cell types upon appropriate stimuli. Subsequently,
p38α
kinase has been shown to be involved in the biosynthesis of
TNFα
and IL-1β at the translational and transcriptional level.
MAP kinase p38α
represents a point of convergence for multiple signaling processes
that are activated in inflammation and thus a key potential
target for the modulation of cytokine production. The discovery
and publication of p38α
and the pyridinyl-imidazole inhibitor initiated a huge effort
by many companies to develop p38α
inhibitors as potential treatment for inflammatory diseases.
Herein we provide a brief overview of recent reported clinical
results for AMG 548, BIRB 796, VX 702, SCIO 469, and SCIO
323. However, our focus will be on the binding modes of these
inhibitors and other p38 inhibitors in the recent literature.
[Back to top]
PPARs in Diseases: Control Mechanisms of Inflammation
Radina Kostadinova, Walter Wahli and Liliane
Michalik
The three isotypes of peroxisome proliferator-activated receptors
(PPARs), PPARα,
β/δ
and γ,
are ligand-inducible transcription factors that belong to
the nuclear hormone receptor family. PPARs are implicated
in the control of inflammatory responses and in energy homeostasis
and thus, can be defined as metabolic and anti-inflammatory
transcription factors. They exert their anti-inflammatory
effects by inhibiting the induction of pro-inflammatory cytokines,
adhesion molecules and extracellular matrix proteins or by
stimulating the production of anti-inflammatory molecules.
Furthermore, PPARs modulate the proliferation, differentiation
and survival of immune cells including macrophages, B cells
and T cells. This review discusses the molecular mechanisms
by which PPARs and their ligands modulate the inflammatory
response. In addition, it presents recent developments implicating
PPAR specific ligands in potential treatments of inflammation-related
diseases, such as atherosclerosis, inflammatory bowel diseases,
Parkinson’s and Alzheimer’s diseases.
[Back to top]
Inhibitors of Secretory Phospholipase A2
Group IIA
Robert C. Reid
Phospholipases A2 cleave membrane phospholipids
to release arachidonic acid, the precursor to a large family
of pro-inflammatory eicosanoids including prostaglandins and
leukotrienes that have been proven to exacerbate numerous
diseases that have an inflammatory component. Current therapies
include NSAIDs’ that inhibit cyclooxygenases (COX-1,
COX-2) but have no effect on the production of leukotrienes
or platelet activating factor (PAF). Inhibitors of PLA2
therefore offer the potential to block production of a more
complete set of inflammatory substances through blockade at
the onset of the cascade of reactions that follow arachidonic
acid release. Many potent, bioavailable and selective inhibitors
of human sPLA2 group IIA have been available for
more than a decade and have provided compelling support for
a causative role of sPLA2 group IIA in numerous
studies involving animal models of inflammatory diseases.
However, the true value of sPLA2 inhibitors for
the treatment of human diseases has had to await phase II
clinical trials which have only been completed in the last
two years. This review presents the structurally diverse array
of available sPLA2 group IIA inhibitors, their
associated biological activity in animal models, and evaluation
of therapeutic potential in phase II clinical trials in humans.
[Back to top]
Nonpeptide Ligands That Target Peptide-Activated GPCRs
In Inflammation
Jade S. Blakeney and David P. Fairlie
The focus of this review is on G protein-coupled receptors
(GPCRs) for which nonpeptidic ligands are known and have been
evaluated for the treatment of inflammatory conditions. GPCRs
are the most prevalent class of cell surface proteins in pharmaceutical
research today, and GPCR-targeting drugs account for one tenth
of worldwide pharmaceutical sales. Of over 800 human GPCRs
identified to date, several hundred are activated by peptides/proteins
and just over 30 of these have been identified so far as potential
therapeutic targets for the treatment of inflammatory diseases.
This review highlights those GPCRs and over 60 structurally
diverse nonpeptidic compounds that interact with them and
display pro- or anti- inflammatory properties. Among these
GPCR targets are the receptors for peptides like bradykinin,
chemokines, complement anaphylatoxins, corticotropin releasing
factor, endothelins, melanocortins, tachykinins, urocortins,
as well as the protease activated receptors (PARs). Other
peptide activated GPCRs implicated in inflammation, like those
that bind angiotensin II, N-formyl peptides, galanin, neuropeptide
Y, opioids and oxytocin, are only briefly discussed because
there is either less direct association with inflammation
or few/no nonpeptidic antiinflammatory ligands known. While
it is still very early in the development of antiinflammatory
drugs that target GPCRs, there is already a wealth of information
supporting their important roles as cellular sentries in inflammatory
diseases. New opportunities are emerging to evaluate antiinflammatory
activities of potent and selective GPCR-binding ligands, including
those being developed for other disease indications. In summary,
GPCRs deserve a great deal more attention as potential therapeutic
targets in inflammatory diseases.
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