Mini-Reviews in Medicinal Chemistry, Volume 5, No. 9, 2005
Contents
Chemokine
Inhibitors as Anti-Inflammatory Drugs
Executive
Editor: David J. Grainger
Editorial Pp.100%-780
David
J. Grainger
Chemokine Signaling Defines Novel Targets for
Therapeutic Intervention
Pp.781-789
Jose
Miguel Rodriguez-Frade, Carlos Martinez-A. and Mario Mellado
BX471: A CCR1 Antagonist with
Anti-Inflammatory Activity in Man Pp.791-804
Richard
Horuk
Potential Clinical Applications of the CXCR4
Antagonist Bicyclam AMD3100
Pp.805-824
Erik
De Clercq
Broad Spectrum Chemokine Inhibitors Related
to NR58-3.14.3 Pp.825-832
David
J. Grainger, Jill Reckless and David J. Fox
Virally Encoded Chemokine Binding Proteins Pp.833-848
Louise
M.C. Webb and Antonio Alcami
The Toxicology of Chemokine Inhibition Pp.849-855
Robert W. Schroff, Caroline Touvay, Michael D. Culler, Jesse Z. Dong, John E. Taylor, Christophe Thurieau and Elaine McKilligin
General Review
Structure-Activity Relationships of p38
Mitogen-Activated Protein Kinase Inhibitors Pp.857-868
Jordi Bolos
Abstracts
[Back to top] Editorial
David
J. Grainger
As if its
importance were not already clear, inappropriate inflammation is getting in on the
act in a whole range of disease processes not previously thought to have an
immunological component central to their pathogenesis. In osteoporosis, for
example, it is now clear that the osteoclast cells, responsible for bone
mineral resorption, are recruited from the circulating monocyte pool. In
Alzheimer’s disease, beneficial effects of non-steroidal, anti-inflammatory
agents might suggest that immune system function participates in the
neurodegenerative process. In heart diseases, the discovery of the role of
chronic inflammation in destabilising the atherosclerotic plaque has led to a gestaltshift
in the way the pathogenesis of the disease is viewed, and in our search for new
therapeutic agents.
Add in the wide
range of diseases where the central role of inappropriate inflammatory
responses was already clear, from autoimmune conditions such as multiple
sclerosis and rheumatoid arthritis to inflammatory bowel disease, psoriasis and
asthma, and the list of diseases potentially amenable to treatment with
anti-inflammatory drugs has become very long indeed.
Inherently,
anti-inflammatory therapeutics tread a fine balance between efficacy and
toxicity: in general, the more powerful the anti-inflammatory effects, the
greater the associated side-effects. At one extreme, we have immunosuppressive
agents (such as cyclosporin or rapamycin) which can completely inhibit
inappropriate inflammation only at the cost of severely impairing the function
of the entire immune system. Glucocorticoids (such as dexamethasone or
hydrocortisone) offer a better trade-off in most circumstances, combining
powerful anti-inflammatory activity with a side-effect profile that is
significant but controllable (at least during acute treatment at lower doses).
The non-steroidal, anti-inflammatory drugs (NSAIDs) such as aspirin,
indomethacin or celecoxib are generally less powerful anti-inflammatory agents,
in most cases blocking inflammatory cell activation, rather than leukocyte
recruitment, but the side-effects are also proportionally less severe than
steroids.
More recently, as
the molecular cues which orchestrate leukocyte traffic both in the healthy
immune system and during pathological inflammation have become clear, new hopes
have been raised that we can design targeted anti-inflammatory drugs which
abolish the pathogenic leukocyte recruitment, without interfering with the
normal immune system function. The chemokine superfamily represents a
particularly attractive target for such intervention, since this network of
more than 50 ligands and 20 receptors plays a central role in the precise
temporal and spatial control of leukocyte recruitment, moving specific subsets
of leukocytes to particular addresses with exquisite accuracy. If the right
combination of chemokine signals could be specifically blocked, it seems
plausible that a particular undesirable inflammatory response could be
attenuated, without causing widespread disruption to the rest of the immune
system.
Given the obvious
appeal of the target and the amount of research effort which has been spent, it
is perhaps surprising that clinically useful chemokine inhibitors have not
emerged before now. Chemokine receptors are members of G-protein coupled
receptor (GPCR) superfamily, which have a good history as successful targets for
the pharmaceutical industry. The long delay from the first emergence of the
central importance of the chemokine family in the early 1990s, to the first
clinical trials of chemokine inhibitors may, in fact, reflect the difficulty in
finding chemokine receptor antagonists with sufficient selectivity (both
compared with receptors for other chemokines and with bioactive amine
receptors). Despite these difficulties, clinical studies with chemokine
inhibitors are finally underway, and early results are encouraging, although
there is still a long way to go before chemokine inhibitors can be considered a
new class of anti-inflammatory drugs in man.
In this issue, the
biology of chemokine receptor signalling which underpins attempts to design
therapeutic inhibitors is extensively reviewed. There are also in depth reviews
of two of the most advanced specific chemokine receptor antagonists (the CCR1
antagonist BX471 and the CXCR4 antagonist AMD3100), as well as the
Broad-spectrum Chemokine Inhibitors (BSCIs) we have developed. A different
approach to chemokine inhibition is the exploitation of ligand-binding proteins
from various viruses which, like the BSCIs, can inhibit the signals from
multiple chemokines simultaneously, and the properties of these viral chemokine
binding proteins are presented. Finally, if chemokine inhibitors are to offer a
substantial clinical benefit over and above existing therapeutic options, then
they need to deliver their promising anti-inflammatory activity with a better
side-effect profile than current drugs. The issue therefore concludes with an
early insight into the limited toxicological information currently available
for chemokine inhibition in vivo, and discusses its implications for the future
development of this broad class of drugs.
[Back to top] Chemokine Signaling Defines Novel Targets for
Therapeutic Intervention
Jose
Miguel Rodriguez-Frade, Carlos Martinez-A. and Mario Mellado
Members of the
human chemokine family are considered a suitable target for therapeutic
intervention, as they have a fundamental role in several important human
diseases. Here we outline potential new areas of intervention based on recent
findings on chemokine receptor function.
[Back to top] BX471: A CCR1 Antagonist with
Anti-Inflammatory Activity in Man
Richard
Horuk
Chemokines belong
to a large family of chemoattractant molecules involved in the directed
migration of immune cells. They achieve their cellular effects by direct interaction
with cell surface receptors. The chemokine receptor CCR1 appears to be involved
in a variety of proinflammatory and autoimmune diseases and this makes it a
very attractive therapeutic target. This review discusses the identification,
chemistry, biology and therapeutic potential of BX 471 a potent CCR1 antagonist
that is currently in the clinic for a variety of indications.
[Back to top] Potential Clinical Applications of the CXCR4
Antagonist Bicyclam AMD3100
Erik
De Clercq
The bicyclam
AMD3100 (originally called JM3100), in which the two cyclam rings are tethered
by an aromatic bridge, emanated from JM2763, where the two cyclam moieties are
tethered by an aliphatic linker – JM2763 in turn originated from JM1657, where
the cyclam rings are directly linked to one another via a C-C bridge, and which
was identified as an impurity, showing anti-HIV activity, in a commercial
cyclam preparation. AMD3100 proved very effective against HIV-1 and HIV-2,
inhibiting virus replication within the nM range, without toxicity for the host
cells at concentrations that were > 100,000-fold higher than those required
to inhibit HIV replication. The anti-HIV activity of AMD3100 appeared to be
confined to the T-lymphotropic (X4) HIV strains, i.e. those strains that use
the CXCR4 receptor to enter their target cells, and AMD3100 as of today still
stands as one of the most potent and selective CXCR4 antagonists ever
discovered. Hence, AMD3100 was found to interfere with a number of (patho)physiological
processes which depend on the interaction of CXCR4 with its natural ligand,
stromal derived factor (SDF-1) and which play an important role in rheumatoid,
allergic and malignant diseases. AMD3100 has been shown to mobilize CD34+ stem
cells from the bone marrow into the bloodstream and has also been shown to
augment migration of bone marrow-derived endothelial progenitor cells into
sites of neovascularization after myocardial infarction. Currently, AMD3100 is
actively pursued as a stem cell mobilizer for transplantation in patients with
multiple myeloma and non-Hodgkin’s lymphoma.
[Back to top] Broad Spectrum Chemokine Inhibitors Related
to NR58-3.14.3
David
J. Grainger, Jill Reckless and David J. Fox
The chemokine
family consists of more than 50 structurally-related small proteins which
signal through type 1 G-protein coupled receptors (GPCRs) to regulate a range
of immune functions, with particular focus on regulating leukocyte trafficking.
They have been implicated both in normal physiological leukocyte traffic, and
in recruitment of leukocytes to sites of pathological inflammation. As a
result, chemokine inhibitors may have useful anti-inflammatory therapeutic
properties in vivo. Compounds with chemokine-inhibitory properties that
have been described to date, fall into two broad categories: receptor-specific
antagonists which block the action of one or a small number of related
chemokines, and broad-spectrum chemokine inhibitors (BSCIs) which block leukocyte
migration in response to many, if not all, chemokines simultaneously. Since
many chemokines apparently show functional redundancy in vivo, the BSCI
class are attractive candidates for development as anti-inflammatory therapies.
Here, we review the development of BSCIs, with particular focus on the design
and characterisation of non-peptide compounds. The key structural requirements
for BSCI activity are discussed, together with their implications for the
mechanism of BSCI action.
[Back to top] Virally Encoded Chemokine Binding Proteins
Virus-encoded
immune evasion mechanisms provide information on viral pathogenesis and offer a
unique opportunity to identify new strategies of immune modulation. Secreted
proteins that bind a broad range of chemokines have been identified in recent
years in poxviruses and herpesviruses. We discuss the properties of these viral
chemokine inhibitors and their potential as new therapeutics to treat human
inflammatory diseases.
[Back to top] The Toxicology of Chemokine Inhibition
Robert
W. Schroff, Caroline Touvay, Michael D. Culler, Jesse Z. Dong, John E. Taylor,
Christophe Thurieau and Elaine McKilligin
The dividing line
between essential physiological inflammatory processes and excessive
pathological inflammation is often very thin – in some circumstances, indeed,
it may be non-existent. Devising anti-inflammatory medications that effectively
target only the pathological component therefore remains a central challenge
for the pharmaceutical industry. At present, the general rule is that the more
powerful the anti-inflammatory effect of a drug, the greater the side-effects
that accompany it. Steroids, for example, are potent anti-inflammatory
medications, but they have a diverse array of side effects that substantially
limit their use. Since chemokines play a central role in regulating the immune
system, and in particular, the trafficking of leukocytes, inhibiting their action
may represent a powerful new therapeutic strategy for treating diseases with an
inflammatory component. However, this potential will only be realized if it is
possible to interfere with chemokine signaling networks, without inducing
unacceptable side effects. Although very little, direct human toxicology has
been carried out using chemokine inhibitors, there is now a sufficient body of
indirect and circumstantial evidence (for example, from genetically modified
mice and from animal model studies using chemokine inhibitors) to allow a
tentative assessment of the biological impact of chemokine inhibition. The
purpose of this review is to outline the available data and to speculate on the
likely toxicological profile resulting from chemokine inhibition. The tentative
conclusion is that anti-inflammatory therapy achieved through chemokine
inhibition may have fewer side effects than originally expected, even when the
actions of multiple chemokines are inhibited simultaneously.
[Back to top] Structure-Activity Relationships of p38 Mitogen-Activated Protein
Kinase Inhibitors
Jordi
Bolos
Rheumatoid
arthritis and other chronic inflammatory diseases constitute a major
therapeutic challenge, usually not sufficiently met by the classical
antiinflammatory medications. Recent research efforts provided new insights
into the molecular basis of these pathologies and disclosed new opportunities
for developing improved drugs directed to the chemical mediators of the
disease. The enzyme p38 MAP kinase plays a central role in the signal
transduction cascade that leads to the production of both the proinflammatory
cytokines, TNF-a and IL-1b,
thus representing an attractive therapeutic target for novel antiinflammatory
therapies. A number of p38 inhibitors belonging to different structural
families have been developed as potential antiinflammatory drugs, and some of
them progressed into clinical trials. The initial pyridinyl imidazole
inhibitors contributed to the identification and characterization of p38 MAP
kinase as the molecular target of these new drugs, and were found to act as
competitive inhibitors at the ATP binding site of the enzyme. A number of
variations in the pyridine and imidazole rings were subsequently introduced.
Other inhibitors structurally unrelated to the pyridinylimidazoles have also
been developed, such as the pyridopyridazinones, diaryl ureas,
aminobenzophenones and aromatic amides. One of these structural classes, the N,N'‑diarylureas,
has been found to interact with a distinct allosteric site of p38 MAP kinase
and requires a deep conformational change prior to binding.