Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 13, 2006
Contents
Targeting G Protein-Coupled 7TM Receptors
in Inflammation
Guest Editor: Dr. Trond Ulven
Editorial Pp. 1317-1318
GluVII:06 - A Highly Conserved and Selective Anchor Point
for Non-Peptide Ligands in Chemokine Receptors Pp.
1319-1333
Mette M. Rosenkilde and Thue W. Schwartz
[Abstract]
Antagonists of CCR4 as Immunomodulatory Agents
Pp. 1335-1344
Ashok V. Purandare and John E. Somerville
[Abstract]
Small Molecule Antagonists of the CXCR2 and CXCR1
Chemokine Receptors as Therapeutic Agents for the Treatment
of Inflammatory Diseases Pp. 1345-1352
Jakob Busch-Petersen
[Abstract]
Advances in the Development of Bradykinin Receptor
Ligands Pp. 1353-1363
Jean-Philippe Fortin and Francois Marceau
[Abstract]
The Emerging Role of the Histamine H4
Receptor in Anti Inflammatory Therapy Pp. 1365-1373
Herman D. Lim, Rogier A. Smits, Rob Leurs and Iwan J.P.
De Esch
[Abstract]
Recent Progress in the Development of Adenosine
Receptor Ligands as Antiinflammatory Drugs Pp. 1375-1399
Rhalid Akkari, Joachim C. Burbiel, Jörg Hockemeyer
and Christa E. Müller
[Abstract]
The Cannabinergic System as a Target for Anti-Inflammatory
Therapies Pp. 1401-1426
Dai Lu, Venkata Kiran Vemuri, Richard I. Duclos, Jr. and
Alexandros Makriyannis
[Abstract]
Targeting the Prostaglandin D2 Receptors
DP and CRTH2 for Treatment of Inflammation Pp. 1427-1444
Trond Ulven and Evi Kostenis
[Abstract]
Abstracts
[Back to top]
Editorial
Inflammation is the natural immune response of the body to
infection or other damage, and is vital to survival. However,
occasionally the inflammatory response is out of proportion
with the tissue damage, and the survival strategy becomes
the problem itself. This is the case with many serious chronic
and acute diseases, like allergy and asthma, inflammatory
bowel disease, multiple sclerosis, rheumatoid arthritis, and
septic shock. It is also established that cancerous diseases,
atherosclerosis, metabolic disorders like diabetes mellitus
and obesity, and CNS disorders such as multiple sclerosis,
Alzheimer’s disease and stroke, involve important inflammatory
components. Even if progress has been made, it is clear that
inflammatory conditions at large still represent a formidable
therapeutic challenge, and it appears safe to forecast that
this will continue to occupy the pharmaceutical industry and
those dedicated to drug discovery into the future.
On a molecular level, the inflammatory response is highly
complex, involving a vast array of messenger molecules interacting
with enzymes and receptors of virtually every class, directing
recruitment of immune cells to eliminate the source of infection
and recover the healthy state. Indeed, absence of inflammation
also involves an active immune system and a balance between
the inflammatory messengers, which together with the inherent
redundancy of the system makes therapeutic intervention a
considerable challenge [1]. A recent issue of this journal
dealt with new approaches to treatment of inflammatory disorders,
and discussed various molecular targets, including synthases,
kinases, nuclear receptors, and targets within the intracellular
secretory pathway.
The G protein-coupled seven-transmembrane receptors, commonly
known as GPCRs, heptahelical receptors or 7TM receptors, make
up a large family of cell surface receptors which are found
on all cell types in the body and are implicated in virtually
every physiological process. Comprising about 200 members
with known endogenous ligands in addition to numerous sensory
and orphan receptors, the 7TM protein superfamily has proven
highly suitable as drug targets, with a substantial fraction
of all marketed drugs exerting their action through members
of this receptor superfamily. The receptors share a number
of characteristic features, including an extracellular N-terminal,
seven transmembrane α-helical
segments, an intracellular C-terminal, and the ability to
activate heterotrimeric G proteins. Despite their common architecture,
the 7TM receptors act as cell surface receptors for highly
diverse endogenous molecules, including large proteins and
small peptides, monoamines, nucleosides, and lipids. Inflammatory
mediators encompass a corresponding structural diversity,
and the contributions in this issue reflect the variety of
these messenger molecules as well as the diversity of endogenous
7TM receptor ligands.
Chemokines are a family of 8-12 kDa proteins which play a
crucial role in directing leukocytes to the site of inflammation
through activation of specific 7TM receptors on the cell surfaces.
In the first article in this issue, Rosenkilde and Schwartz
give an introduction to chemokines and their receptors. They
highlight a specific glutamic acid residue in transmembrane
segment VII which is highly conserved throughout the chemokine
receptor class, but not present in other 7TM receptors, and
propose a simplified general chemokine receptor pharmacophore
of potential utility for future ligand design where this residue
acts as a central anchor point. Representative antagonists
for CCR1, CCR2, CCR3 and CCR5 are discussed in light of this
hypothesis and related to results from site-directed mutagenesis.
In the second article, Purandare and Somerville present the
validation of the chemokine receptor CCR4 as target in inflammatory
and autoimmune diseases, and the current status of small-molecule
CCR4 antagonists. Busch-Petersen concludes the chemokine section
by reviewing the currently known classes of antagonists for
the interleukin 8 receptors CXCR2 and CXCR1, and the effort
to develop these ligands into new antiinflammatory drugs.
Only a tenth the size of the chemokines, bradykinin and related
small peptides act as pro-inflammatory autacoids through the
receptors B1 and B2. Fortin and Marceau
review the kallikrein-kinin system, the validation of the
two kinin receptors as anti-inflammatory targets, the current
status on development of selective peptide and non-peptide
modulators of these receptors, and the outlook for developing
new drugs from these.
Scaling down the size of the messenger molecule by another
order of magnitude, histamine is a well-known mediator of
allergic and inflammatory responses. Currently, four 7TM receptor
subtypes are known for this monoamine, and the two first of
these, H1R and H2R, have served as targets
for classical anti-allergy and anti-ulcer blockbuster drugs,
respectively. Lim, Smits, Leurs and De Esch review the biochemistry
and the discovery of ligands for the recently identified receptor
H4R, and discuss its implication in inflammation
and its prospects as drug target for a number of inflammatory
diseases.
The ubiquitous nucleoside adenosine is released during inflammatory
reactions and plays an important role in controlling the response.
In a comprehensive review, Akkari, Burbiel, Hockemeyer and
Müller describe the adenosine receptor system, which
includes the receptors A1, A2A, A2B
and A3, and discuss their validation as antiinflammatory
targets. New ligands which have appeared during the last three
years are reviewed, and the status of the most progressed
candidates are examined.
Metabolites of arachidonic acid play central roles in regulation
of inflammatory responses. The endocannabinoid arachidonic
acid derivatives anandamide and 2-arachidonylglycerol signal
through the receptors CB1 and CB2. Whereas the first receptor
is expressed in high levels in the CNS, the latter is predominantly
found in the periphery, and in especially high levels in the
immune system and on immune cells. Lu, Vemuri, Duclos and
Makriyannis review the endocannabinoid system, its effects
on the immune functions and the therapeutic potential for
specific inflammatory diseases, and examine the currently
known classes of CB1 and CB2 agonists and antagonists for
their potential to serve as future antiinflammatory drugs.
Leukotrienes and prostaglandins make up other classes of endogenous
arachidonic acid metabolites with members which are important
players in inflammatory responses. Prostaglandin D2
is one such member which is implicated in asthma and allergy
and for which the receptors DP and CRTH2 have been identified.
In the last article of this issue, Ulven and Kostenis recapitulate
the evidence connecting these receptors to inflammatory conditions,
and review the currently known classes of ligands for these
receptors.
The contributors to this issue were invited with the aim to
broadly reflect the most relevant and interesting 7TM targets
in inflammation, and I would like to thank all authors for
excellent contributions. The intersection between inflammation
and 7TM receptors is still much too broad to be fully covered
in only one issue, and many highly interesting targets are
left out here. Some of these have been covered elsewhere.
The abovementioned issue of CTMC featured a review of the
antiinflammatory neuropeptides VIP and PACAP, which signal
through family B 7TM receptors [2]. In another recent and
highly relevant review, Blakeney and Fairlie cover broadly
non-peptide ligands of inflammatory peptide receptors [3].
Furthermore, there are many novel potential antiinflammatory
targets for which there is not yet any medicinal chemistry
available. Altogether, recent results promising novel antiinflammatory
drugs through intervention with 7TM targets are abundant,
and it will be exciting to follow the development.
[1] Nathan, C. Points of control in inflammation. Nature
2002, 420, 846-852.
[2] Abad, C.; Gomariz, R. P.; Waschek, J. A. Neuropeptide
mimetics and antagonists in the treatment of inflammatory
disease: focus on VIP and PACAP. Curr. Top. Med. Chem.
2006, 6, 151-163.
[3] Blakeney, J. S.; Fairlie, D. P. Nonpeptide ligands that
target peptide-activated GPCRs in inflammation. Curr.
Med. Chem. 2005, 12, 3027-3042.
Dr. Trond Ulven
Department of Chemistry,
University of Southern Denmark,
Campusvej 55,
DK-5230 Odense M,
Denmark
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GluVII:06 - A Highly Conserved and Selective Anchor
Point for Non-Peptide Ligands in Chemokine Receptors
Mette M. Rosenkilde and Thue W. Schwartz
A majority of small molecule non-peptide ligands for chemokine
receptors in general are characterized by the presence of
one or two centrally located, positively charged nitrogen
atoms and these compounds are also often of relatively similar
elongated overall structure with terminal aromatic moieties.
In the corresponding main ligand-binding crevice of the chemokine
7TM receptors is found a centrally located glutamic acid residue
in position 6 of transmembrane segment VII in 74% of the chemokine
receptors but only in approx. 1% of non-chemokine receptors.
GluVII:06 has been demonstrated to be crucially important
for the binding and action of a number of non-peptide ligands
in for example the CCR1, CCR2 and CCR5 receptors. It is proposed
that in chemokine receptors in general GluVII:06 serves as
a selective anchor point for the centrally located, positively
charged nitrogen of the small molecule ligands and that the
two peripheral chemical moieties of the ligands from this
central point in the receptor structure explore each of the
two halves of the main ligand binding pocket. It is envisioned
that knowledge of this binding mode can be exploited in structure-based
discovery and design of novel chemokine receptor ligands and
especially ligands with specifically optimized properties.
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Antagonists of CCR4 as Immunomodulatory Agents
Ashok V. Purandare and John E. Somerville
The chemokine receptor CCR4 is broadly expressed on cells
of the immune system. It is known to play a central role in
T cell migration to the thymus, and T cell maturation and
education. In addition, CCR4 is known to modulate T cell migration
to several sites of inflammation in the body, including the
skin, and lungs. It is best known as a drug target for airway
inflammation and atopic dermatitis, but cells expressing CCR4
are found in many inflammatory diseases. CCR4 small molecule
antagonists have not yet reached the clinic, but at least
one has been validated in an in vivo model. Here
we review the current status of structurally novel CCR4 receptor
antagonists.
[Back to top]
Small Molecule Antagonists of the CXCR2 and CXCR1
Chemokine Receptors as Therapeutic Agents for the Treatment
of Inflammatory Diseases
Jakob Busch-Petersen
In the past eight years, numerous series of small molecule
CXCR2 and CXCR1 antagonists have been disclosed. These compounds
have proved to be effective inhibitors of ELR+ chemokine-induced
chemotaxis of neutrophils and other immune cells in vitro
and have also been efficacious in several animal models of
inflammatory disease. Although some of these compounds have
been reported to be in clinical development, no data on clinical
studies in patients with inflammatory disease has been revealed
to date. This review details the medicinal chemistry and pharmacology
of the aforementioned antagonist series.
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Advances in the Development of Bradykinin Receptor
Ligands
Jean-Philippe Fortin and Francois Marceau
Kinins are blood-derived local-acting peptides that elicit
specific cellular effects via the stimulation of two related
G protein coupled receptors. While the B2 receptor
subtype, constitutively expressed in various tissues, is believed
to mediate most of the physiological actions of kinins in
healthy conditions, the B1 receptor, highly regulated
during inflammation, has been associated with the sustained
actions of these peptides in various pathological situations.
Potent peptide and nonpeptide modulators of both kinin receptors
have been produced as pharmacological tools and potential
therapeutics over the last three decades. More recently, the
accumulating evidence suggesting that B1 receptor
blockade could be useful for the treatment of pain and inflammatory
disorders has led to a shift in drug development efforts toward
the synthesis of orally bioavailable nonpeptide B1
receptor antagonists. Nonpeptide ligands of either receptor
subtype produced by several industrial organizations often
possess significant structural commonalities that can lead
to the definition of a pharmacophore, especially when the
receptor docking models are compared. The field of kinin receptors
ligands research has reached an exciting step of its history,
as the near future will reveal whether these molecules are
therapeutically beneficial in various human diseases. This
review will concisely summarize our current understanding
of the biology of kinins and their receptors, before discussing
the recent medicinal chemistry developments and challenges
that bring new kinin receptor ligands closer to clinical applications.
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The Emerging Role of the Histamine H4
Receptor in Anti Inflammatory Therapy
Herman D. Lim, Rogier A. Smits, Rob Leurs and Iwan J.P.
De Esch
Antagonists for the Histamine H1 receptor have
been on the market for decades and continue to be successfully
used in the treatment of a variety of allergic conditions.
The recently discovered histamine H4 receptor subtype
is emerging as a new and complementary target for treating
inflammatory conditions. In this review, we describe the receptor
protein, its putative role in (patho)physiology and the latest
ligands that are being developed to explore the feasibility
of the H4 receptor as a drug target.
[Back to top]
Recent Progress in the Development of Adenosine
Receptor Ligands as Antiinflammatory Drugs
Rhalid Akkari, Joachim C. Burbiel, Jörg Hockemeyer
and Christa E. Müller
Adenosine receptors belong to the family of G protein-coupled
receptors. Four distinct subtypes are known, termed A1,
A2A, A2B and A3. Adenosine
is an important signaling molecule which is released under
inflammatory conditions. It can show antiinflammatory as well
as proinflammatory activities, and the contribution of the
specific adenosine receptor subtypes in various cells, tissues
and organs is complex. Agonists selective for adenosine A1
receptors show antinociceptive activity and are active in
animal models of neuropathic and inflammatory pain. Adenosine
A2A receptor agonists are potent antiinflammatory
drugs. A2A-selective antagonists have shown antihyperalgesic
activity in animal models of inflammatory pain. For A2B
agonists as well as A2B antagonists antiinflammatory
activity has been postulated. Selective A2B antagonists
were shown to decrease (inflammatory) pain, and are promising
candidates for the treatment of asthma. Adenosine A3
receptor agonists appear to be proinflammatory, while there
is evidence for an antiinflammatory effect of A3
antagonists. There are some contradictory findings, and A3
agonists are being developed for the treatment of inflammatory
diseases such as arthritis. Indirect mechanisms increasing
the extracellular concentration of adenosine using adenosine
kinase inhibitors, adenosine deaminase inhibitors or adenosine
uptake inhibitors, or increasing the potency of adenosine
at the A1 receptor subtype by allosteric modulators
lead to potent antinociceptive and antiinflammatory activity.
The advantage of indirectly acting drugs may be their site-
and event-specific action since they are only active where
adenosine has been released. In the past decade considerable
progress has been made towards the identification of novel
lead structures and the development of potent and selective
ligands for all four adenosine receptor subtypes. A large
number of patents has recently been filed and the field is
finally in the process of translating many years of basic
science into therapeutic application. This review article
will focus on compounds published or patented within the past
three years.
[Back to top]
The Cannabinergic System as a Target for Anti-Inflammatory
Therapies
Dai Lu, Venkata Kiran Vemuri, Richard I. Duclos, Jr. and
Alexandros Makriyannis
Habitual cannabis use has been shown to affect the human immune
system, and recent advances in endocannabinoid research provide
a basis for understanding these immunomodulatory effects.
Cell-based experiments or in vivo animal testing
suggest that regulation of the endocannabinoid circuitry can
impact almost every major function associated with the immune
system. These studies were assisted by the development of
numerous novel molecules that exert their biological effects
through the endocannabinoid system. Several of these compounds
were tested for their effects on immune function, and the
results suggest therapeutic opportunities for a variety of
inflammatory diseases such as multiple sclerosis, rheumatoid
arthritis, inflammatory bowel disease, atherosclerosis, allergic
asthma, and autoimmune diabetes through modulation of the
endocannabinoid system.
[Back to top]
Targeting the Prostaglandin D2 Receptors
DP and CRTH2 for Treatment of Inflammation
Trond Ulven and Evi Kostenis
The involvement of prostaglandin D2 (PGD2)
in inflammatory diseases like allergy and asthma is well established,
thus blocking the effect of this mediator represents a novel
therapeutic approach for the treatment of such diseases. PGD2
is now known to act through two seven-transmembrane (7TM)
receptors, DP (DP1) and CRTH2 (DP2),
which are also activated by several endogenous metabolites
from the arachidonic acid cascade, making the regulatory system
highly complex. There has recently been a considerable effort
aimed at developing antagonists of the PGD2 receptors
for treatment of inflammatory conditions like asthma and rhinitis.
Several potent DP antagonists are now known, and one of these
is currently in clinical trials for treatment of asthma. CRTH2
has received much attention since its identification as the
second high affinity PGD2 receptor in 2001, and
a number of potent and selective antagonists have recently
become available. This review will briefly discuss the biological
background and validation of DP and CRTH2 as targets for antiinflammatory
drugs, and then highlight developments in medicinal chemistry
which have appeared in journals and patent applications in
the last few years, and which have brought us closer to therapeutic
applications of PGD2 receptor antagonists in various
indications.
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