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Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
ISSN: 1871-5230
Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
Volume 5, Number 1, February 2006
Contents
Cellular and Molecular Mechanisms of Action
of Drugs Affecting Inflammatory Leukocyte Function
Guest Editor: P.X. Elsas
Editorial Pp. 1-2
Granulocyte Apoptosis and Macrophage Clearance of
Apoptotic Cells as Targets for Pharmacological Intervention
in Inflammatory Diseases Pp. 3-12
N.A. Riley, C. Ward, D.A. Sawatzky, T.A. Sheldrake, I.
Dransfield, C. Haslett and A.G. Rossi
[Abstract]
Anti-Inflammatory Drug Effects on Apoptosis of Eosinophil
Granulocytes Derived from Murine Bone-Marrow: Cellular Mechanisms
as Related to Lineage, Developmental Stage and Hemopoietic
Environment Pp. 13-25
M.I.C.G. Elsas and P.X. Elsas
[Abstract]
Apoptosis and Atherosclerosis: The Role of Nitric Oxide Pp.
27-33
C.A. Shaw, I.L. Megson and A.G. Rossi
[Abstract]
Inflammatory and Vascular Alterations in Sepsis: The
Role of Nitric Oxide-Dependent Mechanisms Pp. 35-44
J. Assreuy, F. de Queiroz Cunha, C. Barja-Fidalgo
and B.M. Tavares-Murta
[Abstract]
Modulation of Eosinophil Functions by Nitric Oxide:
Cyclic GMP-dependent and –independent Mechanisms
Pp. 45-57
H.H.A. Ferreira, N. Conran and E. Antunes
[Abstract]
Signaling Pathways Involved in Leukocyte Adhesiveness
and Migration during Inflammation: Potential Targets for Therapeutic
Interventions? Pp. 59-69
C. Barja-Fidalgo, M.A.C. Arruda, R. Saldanha-Gama and
M.S. de Freitas
[Abstract]
Thalidomide: An Overview of its Pharmacological Mechanisms
of Action Pp. 71-77
E.P. Sampaio, D.S. Carvalho, J.A.C. Nery, U.G. Lopes and
E.N. Sarno
[Abstract]
Thalidomide and Analogs as Anti-inflammatory and Immunomodulator
Drug Candidates Pp. 79-95
L.M. Lima, C.A.M. Fraga, V.L.G. Koatz and E.J. Barreiro
[Abstract]
Abstracts
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Editorial
Dept. of Immunology, Instituto de Microbiologia Prof. Paulo
de Goes, UFRJ, Rio de Janeiro, Brazil; and Depts. of Medicine,
Brigham and Women’s Hospital and Harvard Medical School,
Boston, MA, USA; E-mail: pxelsas@yahoo.com.br
While it is often repeated that one cannot teach an old dog
new tricks, it is likely that one can learn new tricks even
from an old dog; and the same is certainly true for old drugs,
as abundantly illustrated by the review articles in this special
issue of Current Medicinal Chemistry.
Even though most of them deal with very timely issues of cellular
and molecular mechanism in the context of inflammation, much
of the information discussed has been obtained with the help
of pharmacological tools that are in some cases more than
a century old, like aspirin [1], or which have been in constant
use and study for as long as five decades, like the glucocorticoids
[2]. In other examples, the field of investigation, rather
than the specific pharmacological tool, is time-honored: the
study of snake venoms in pharmacology has led to the seminal
discovery of bradykinin and the development of a whole class
of anti-hypertensive agents, dating back to the studies of
brazilian pharmacologist Mauricio Rocha e Silva and his collaborators
in the 1940’s [3]. The more recent discovery of disintegrins
and the development of novel analogues of snake venom disintegrins
which have an impact on inflammation, in addition to effects
on hemostasis, are among the most striking examples of the
enormous potential of venoms as sources of powerful biological
probes [4]. Another time-honored field is that of nitric oxide
(NO) biology, which largely antedates the identification of
NO itself as a central effector in biological processes as
different as the control of vascular tone, inhibition of platelet
aggregation, killing of intracellular microorganisms by macrophages
and wound healing [5-8]: sodium nitroprusside, the effects
of which are mediated by NO, was characterized as an anti-hypertensive
agent in 1929 and became a standard treatment for acute control
of severe hypertension in the 1950’s [9].
The articles gathered in this special issue follow either
one or the other of these patterns. They either concentrate
on old drugs that have unexpected effects when tested in novel
systems, or they explore novel aspects of mediators that have
been intensively studied over a long time, such as NO and
snake venoms. Sometimes, they do both. It is clear that important,
novel information continues to be generated through both approaches.
This suggests that important advances in medicinal chemistry
can be made by combining the properties of well-characterized
agents available today.
The reviews by Riley and colleagues [10] and Gaspar-Elsas
and Elsas [11] in this issue provide an example of the first
pattern. They review the effects of a number of well-known
agents on granulocytes from opposite standpoints: while Riley
and colleagues concentrate on the mature granulocytes of the
neutrophil and eosinophil lineage, found in peripheral blood
and inflammatory sites, Gaspar-Elsas and Elsas analyse the
development of eosinophils in bone-marrow and other sites
from hemopoietic progenitors and precursors. Even though their
reviews address the two extremes of a leukocyte’s life
cycle, they are closely related by their emphasis in the ubiquitous
process of apoptosis. From their contributions, it is clear
that apoptosis plays a major role in the regulation of granulocyte
numbers, by influencing both production and consumption. The
mass of work they summarize also sheds novel life on the actions
of inflammatory mediators and anti-inflammatory drugs, which
are shown to influence granulocyte survival by acting at key
steps in the control of apoptosis. However, such effects are
also seen to depend strongly on the developmental stage of
the cell being studied, so that certain agents, such as glucocorticoids,
may affect apoptosis in strikingly different ways, depending
on whether one looks at a mature or an immature cell. This
adds a biological dimension to a field in which the response
to a drug or mediator is often assumed to be solely determined
by the presence of the ligand, its receptor and the corresponding
signalling/effector elements.
On the other hand, the articles by Shaw et al. [12],
Assreuy et al. [13] and Ferreira et al.
[14] exemplify the second pattern: they are linked by their
common effort to highlight novel aspects of NO, which is as
physiologically versatile as it is structurally simple. According
to Shaw et al., adequate manipulation of NO in atherosclerotic
lesions may provide a much-needed means of controlling the
progression of life-threatening atherosclerotic plaques. This
view is linked to the increasing perception of atherosclerotic
plaques as the product of a very special type of chronic inflammation.
The target cells for NO, in this case, are the peculiar macrophages
(“foam cells”) that feed the chronic inflammatory
response. On the other hand, Assreuy et al. show
that adequate manipulation of NO equally holds promise for
the control of sepsis, which remains a major challenge in
intensive care medicine, since advances in the understanding
of its pathophysiology have yet to be paralleled by therapeutic
advances leading to a significant reduction of mortality.
In this case, neutrophil granulocytes and endothelial cells
are the primary targets of NO. Finally, Ferreira et al.
review the evidence that NO is central for the control
of eosinophil migration and function in sites of allergic
inflammation, and provide novel insights into its cellular
mechanisms of action. Together, atherosclerosis, sepsis and
allergy represent three of the most important areas in biomedical
research today. There certainly is a high prize for those
achieving adequate control of NO levels at inflammatory sites,
so that the beneficial effects of NO will not be offset by
the harmful consequences of its excess. The very detailed
biochemical and pharmacological information given in all three
articles suggests that such a goal can be eventually achieved.
However, the challenge remains impressive enough: NO is readily
diffusible, reacts rapidly with a number of other moieties
present in inflammatory sites, yielding biologically active
derivatives, and acts on a variety of inflammatory and noninflammatory
cells. Accordingly, to achieve the proposed goal, one should
be able to control NO production and/or delivery which such
precision that only certain cell types in specific locations
would be affected. This challenge may face medicinal chemistry
as well: the evidence reviewed indicates that many different
chemical species release NO in tissues, but do so in many
different ways. Perhaps the desired fine control can be achieved
with the appropriate combination of NO-releasing agents.
Following the same pattern, the review by Barja-Fidalgo and
colleagues [15] illustrates the extent to which the time-honored
study of snake venoms can contribute to the understanding
of inflammatory cell function, and to the development of novel
strategies directed at controlling inflammation by targeting
leukocytes. The review provides a detailed analysis of the
intracellular signalling pathways involved in leukocyte migration,
which illustrates how many different processes that are sometimes
thought of as being separable, such as migration, adhesion
and activation of secretory and microbicidal function, are
extremely intertwined in the living cell. Accordingly, any
agent interfering with one aspect of leukocyte migration is
likely to have an effect on its other effector functions;
while this shows the limits of therapeutic selectivity, it
also encourages us to look for active molecules among those
available today, as is the case with disintegrins.
The two last contributions, those from Sampaio et al.
[16] and Lima et al. [17], provide powerful examples
of how an old drug can perform surprising new tricks. Thalidomide
was not only an old drug; it was also associated with such
tragic teratogenic consequences as to be rightfully banned
from medical practice, with a few exceptions. However, from
its use in the treatment of reactional episodes in leprosy
it gradually regained general attention, as its mechanism
of action was shown to involve regulation of Tumor Necrosis
Factor production. Recent work reviewed in both articles shows
that thalidomide, rather than being old or dead, faces a promising
career ahead, as an adjuvant in the treatment of chronic inflammatory
diseases as well as malignancies. Here, perhaps even more
than in the other questions covered, lies a challenge to medicinal
chemistry: is it possible to generate a thalidomide derivative
that keeps its beneficial actions but not its teratogenicity?
The detailed review of the medicinal chemistry aspects of
the drug, by Lima et al., is especially enlightening in this
respect, since the answer depends on many variables linked
to the structure of the drug as well as to differences in
the way it is metabolized in different animal species.
When one looks at the ensemble of these contributions, one
cannot help being impressed by the amount of information at
the cellular (and sometimes molecular) level that already
exists, concerning the way these different agents affect inflammatory
cells. One is, however, also struck by the feeling that major
gaps remain in our knowledge. What are the determinants of
the overall response of a given cell type (apoptosis, increased
survival, migration), at a given moment in its life cycle,
to a specific drug or inflammatory mediator? What defines
the amount of a critical mediator such as NO present at a
given time in a specific site (or systemically) and thereby
promotes recovery, or offsets the host’s defense mechanisms?
It is hoped that by presenting in a systematic way the existing
knowledge on these issues, this special issue will appeal
to other scientists, who may respond to it by taking up the
challenge presented by these persisting questions, which are
perhaps the oldest of all.
REFERENCES
[1] Roberts II, L. J.; Morrow, J. D. Chapter 27 in Hardman,
J. G.; Limbird, L. E. (Eds.), Goodman & Gilman’s
The pharmacological basis of Therapeutics, 10th.
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[2] Schimmer, B. P.; Parker, K. L. Chapter 60 in Hardman,
J. G.; Limbird, L. E. (Eds.), Goodman & Gilman’s
The pharmacological basis of Therapeutics, 10th.
Ed., Mc Graw-Hill, 2001, pp.1649-1677
[3] Ferreira, S. H. Semin. Perinatol., 2000,
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[4] Calvete, J. J.; Marcinkiewicz, C.; Monleon, D.; Esteve,
V.; Celda, B.; Juarez, P.; Sanz, L. Toxicon, 2005,
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[5] Ignarro, L. J.; Cirino, G.; Casini, A.; Napoli, C.
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[6] Moncada, S.; Palmer, R. M., Higgs, E. A. Pharmacol.
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[7] Dedon, P. C.; Tannenbaum, S. R. Arch. Biochem. Biophys.
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[8] Rizk, M.; Witte, M. B.; Barbul, A. World J. Surg.
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[9] Oates, J. A.; Brown, N. J. Chapter 33 in Hardman, J.
G.; Limbird, L. E. (Eds.), Goodman & Gilman’s
The pharmacological basis of Therapeutics, 10th.
Ed., Mc Graw-Hill, 2001, pp. 871-900
[10] Riley, N. A.; Ward, C.; Sawatzky, D. A.; Sheldrake,
T. A.; Dransfield, I.; Haslett, C.; Rossi, A. G. Curr.
Med. Chem., 2005 (this issue).
[11] Gaspar-Elsas, M. I.; Xavier-Elsas, P. Curr. Med.
Chem., 2005 (this issue).
[12] Shaw, C. A.; Megson, I. L.; Rossi, A. G. Curr. Med.
Chem., 2005 (this issue).
[13] Assreuy, J.; Cunha, F. Q.; Barja-Fidalgo, C.; Tavares-Murta,
B. M. Curr. Med. Chem., 2005 (this
issue).
[14] Ferreira, H. H. A.; Conran, N.; Antunes, E. Curr.
Med. Chem., 2005 (this issue).
[15] Barja-Fidalgo, C.; Arruda, M. A. C.; Saldanha-Gama,
R.; Sampaio de Freitas, M. Curr. Med. Chem.,
2005 (this issue).
[16] Sampaio, E. P.; Serra, D. C.; Nery, J. A.; Lopes, U.
G.; Sarno, E. N. Curr. Med. Chem., 2005
(this issue).
[17] Lima, L. M.; Fraga, C. A. M.; Koatz, V. L. G.; Barreiro,
E. J. Curr. Med. Chem., 2005 (this
issue).
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Granulocyte Apoptosis and Macrophage Clearance of
Apoptotic Cells as Targets for Pharmacological Intervention
in Inflammatory Diseases
N.A. Riley, C. Ward, D.A. Sawatzky, T.A. Sheldrake, I.
Dransfield, C. Haslett and A.G. Rossi
A subset of leukocytes, known as the granulocytes, are the
body’s first line of innate immune defense. The granulocytes
are comprised of neutrophils, eosinophils and basophils of
which the former two will be the focus of this review. Neutrophils
defend the body against bacterial and fungal infection whilst
eosinophils are thought to defend against parasitic invasions.
Granulocytes are recruited to the site of infection or tissue
damage where their relatively short half-life can be extended
by regulatory external factors including hypoxic environments
or agents that activate signaling pathways, such as NF-κB
which is implicated in the up-regulation of anti-apoptotic
genes. Granulocytes release various proteins, proteolytic
enzymes and toxic oxygen products into the phagolysosome or
surrounding environment destroying the invading organism.
However, in order for inflammation to be resolved it is essential
that granulocytes die by apoptosis and are phagocytosed by
macrophages in a non-inflammatory fashion. This prevents the
release of the cell’s histotoxic contents into the extracellular
milieu thereby reducing the potential for tissue damage. In
instances when granulocytes fail to appropriately enter apoptosis
or a defect in phagocytic clearance occurs the inflammatory
response can be perpetuated, potentially resulting in the
development and promotion of inflammatory disorders such as
asthma or rheumatoid arthritis. Thus, selective enhancement
of apoptosis and augmentation of macrophage clearance could
allow targeting of inflammatory resolution to provide potential
novel therapeutic agents for the treatment of inflammatory
dis-orders.
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Anti-Inflammatory Drug Effects on Apoptosis of Eosinophil
Granulocytes Derived from Murine Bone-Marrow: Cellular Mechanisms
as Related to Lineage, Developmental Stage and Hemopoietic
Environment
M.I.C.G. Elsas and P.X. Elsas
The effects of a variety of widely used anti-inflammatory
agents (dexamethasone, indomethacin, and montelukast) as well
as ubiquitous mediators of inflammation (prostaglandin E2
and nitric oxide) on the development of murine eosinophils
ex vivo and in vivo have been studied over
the last decade. The results indicate that developing eosinophils
differ markedly in their responses to these agents from the
mature forms of the same lineage, studied either in allergic
human subjects or experimental animal models of allergic disease.
Most strikingly, glucocorticoids strongly enhance eosinophil
development, both in vitro and in vivo. The
enhancing effects are also observed during stress reactions
and are strictly dependent on stress-induced glucocorticoid
hormone production from the adrenal glands. Some, but not
all, of the developmental effects of glucocorticoids on eosinophils
could be accounted for their ability to prevent generation
of nitric oxide through inducible NO synthase, which leads
to apoptosis through the CD95-CD95L pathway. A novel mechanism
for the effects of indomethacin in upregulating the development
of eosinophils has also been documented. Evidence that lineage-specific
as well as stage-specific cellular response programmes determine
these different outcomes is discussed, along with the perspectives
for future research.
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Apoptosis and Atherosclerosis: The Role of
Nitric Oxide
C.A. Shaw, I.L. Megson and A.G. Rossi
Atherosclerosis, and its associated complications, are a
major cause of morbidity and mortality, and it is now recognised
as a chronic inflammatory disorder. Progression of inflammation
depends on the balance between recruitment of inflammatory
cells and their subsequent removal from a site of inflammation.
Apoptosis, or programmed cell death, is a fundamental process
governing cell survival and is a major determinant of the
resolution of the inflammatory response. Apoptotic cells are
instantly recognised for non-inflammatory clearance by phagocytes
(e.g. macrophages) and removed from the vicinity of inflammation
without the release of their pro-inflammatory cell contents.
Nitric oxide (NO) plays an important role in many biological
processes and has several anti-atherogenic properties including
vasodilatation, inhibition of platelet activation and aggregation,
and the regulation of apoptosis in a variety of cell types
involved in atherogenesis. A critical early event during atherogenesis
is injury to the endothelium. The ensuing damage results in
endothelial dysfunction, including a reduction in the capacity
of the endothelium to generate NO. Decreased NO bioavailability
is likely to influence many cellular processes occurring within
atherosclerotic lesions, including apop-tosis. Modulation
of apoptosis is a novel target for therapeutic intervention
in the treatment of chronic inflammatory dis-orders, such
as atherosclerosis. This modulation may help limit or resolve
inflammation without the concomitant re-cruitment of subsequent
inflammatory cells, thereby reducing the potential for further
tissue damage. NO is a possible candidate for manipulation
of atherosclerotic processes due to both its powerful anti-atherogenic
characteristics and abil-ity to affect apoptosis. This review
highlights the role of apoptosis in atherosclerosis and discusses
the therapeutic po-tential of NO to limit and/or resolve vascular
inflammation.
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Inflammatory and Vascular Alterations in Sepsis: The
Role of Nitric Oxide-Dependent Mechanisms
J. Assreuy, F. de Queiroz Cunha, C. Barja-Fidalgo
and B.M. Tavares-Murta
Sepsis and septic shock continue to be a major cause of
morbidity and mortality in critically ill patients. During
the onset of sepsis, a massive inflammatory reaction is mediated
via cell-derived cytokines and chemokines that target
end-organ receptors in response to injury or infection. Polymorphonuclear
leucocytes are critical effector cells during the inflammatory
process and their migration to the infectious focus is extremely
important for the local control of bacterial growth and consequently
for the prevention of bacterial dissemination. In addition
to the inflammatory process, sepsis and septic shock cause
a profound loss in the peripheral vasomotor tone resulting
in a huge decrease in the peripheral resistance, a central
event in the derangement of hemodynamic and perfusional parameters.
Nitric oxide (NO) is a sim-ple molecule produced by numerous
cell types that has been implicated in a wide range of physiological
and pathologi-cal processes, exerting both detrimental and
beneficial effects. It is an important modulator of neutrophil
adherence and activation, of cardiovascular homeostasis and
end organ perfusion. The induction of the inducible isoform
of NO syn-thase leads to an increased NO production which
is involved both in the impairment of neutrophil migration
and in the cardiovascular disfunction present in sepsis and
septic shock. Thus, a better knowledge of the role of NO in
the inflam-matory, cardiovascular and immune aspects of sepsis
may provide us with more efficient therapeutic alternatives
to treat sepsis and septic shock.
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Modulation of Eosinophil Functions by Nitric Oxide:
Cyclic GMP-dependent and –independent Mechanisms
H.H.A. Ferreira, N. Conran and E. Antunes
Recruitment of eosinophils into tissues is a feature of a
variety of allergic diseases, including asthma and nasal allergy.
Eosinophils secrete several preformed granule proteins (eosinophil
peroxidase, major basic protein, eosinophil cationic protein
and eosinophil-derived neurotoxin) and newly-generated substances
(oxygen-derived toxic metabolites, lipid mediators, cytokines
and chemokines), which may contribute to the exacerbation
of the allergic diseases. In the past decade, NO has been
recognized as a major immunomodulatory mediator of inflammatory
responses, particularly in the lung, where it is believed
to play a pivotal role in modulating pulmonary eosinophilia
and airways hyperresponsiveness in both allergic animals and
humans, as evidenced by functional, biochemical and immunohistochemical
studies. The NO-cGMP signaling cascade was initially implicated
in the modulation of eosinophil functions; however, additional
studies have demonstrated that direct cGMP-independent mechanisms
may also play important roles in eosinophil functions. Much
progress in understanding the influence of NO on eosinophil
functions has been achieved with the use of selective and
non-selective NOS inhibitors, as well as NO-donor compounds,
along with NOS isoform gene knock-out mice. However, these
studies have resulted in numerous controversies and conflicting
findings, possibly as a consequence of the diversity of experimental
models used, animal species employed, methods of immunization
and chal-lenge with allergens, amongst others. The present
review summarizes the role of NO in modulating, in vivo
and in vitro, eosinophil adhesion, chemotaxis, airways
hyperresponsiveness and apoptosis, outlining the conflicting
findings in the literature, with emphasis on the allergic
inflammatory responses.
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Signaling Pathways Involved in Leukocyte Adhesiveness
and Migration during Inflammation: Potential Targets for Therapeutic
Interventions?
C. Barja-Fidalgo, M.A.C. Arruda, R. Saldanha-Gama and
M.S. de Freitas
In response to a chemotactic gradient of inflammatory mediators
and chemokines, neutrophils adhere to vascular endothelium
and directly migrate, leaving blood vessels, toward inflamed
tissue areas, to exert their primary defense function. These
events are mediated by distinct classes of cell surface receptors
in human neutrophils, that not only drive cell adhesion and
motility, but also interfere with the cell’s activation
status, modulating different functions and survival. In this
review we summarize the current understanding of the series
of events that begins at the level of G-protein coupled receptor
activation by chemoattractants, and the signaling pathways
triggered by cell adhesion molecule interactions that lead
to neutrophil adhesion, migration and activation during inflammation.
Integrins, as adhesion receptors able to act as anchoring
molecules (allowing firm cellular attachment to the ECM) and
signaling receptors (transducing signals in both directions,
outside-in and inside-out) are targets that potentially provide
both therapeutic and diagnostic opportunities. We also present
data obtained with integrin-selective ligands, the disintegrins,
which could be useful tools to understand cellular processes
as adhesion, migration, proliferation, activation and cell
survival and may be also suggested as prototypes for designing
therapeutic agents for the prevention or activation of integrin-mediated
effects.
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Thalidomide: An Overview of its Pharmacological Mechanisms
of Action
E.P. Sampaio, D.S. Carvalho, J.A.C. Nery, U.G. Lopes and
E.N. Sarno
Novel discoveries in medicine have provided understanding
of the mechanisms involved in the development and maintenance
of pathologies, thereby leading to the identification of new
therapeutic targets and consequently new drugs. Thalidomide,
independently of its teratogenic effects, is one drug able
to regulate the immune system. Deeper studies about thalidomide
have started on the 90’s, when some of its action mechanisms
were elucidated. Following the initial description of high
systemic TNF-α
production in patients with erythema nodosum leprosum (ENL),
and the reduction of TNF-α
caused by the administration of thalidomide in these patients,
the drug was shown to present multiple effects, making it
difficult to understand the mechanism of its successful use
in some pathologies. Such studies have extended the rational
application of thalidomide to various disorders in which the
participation of one or more factors modulated by the drug
has been related. In this review, we describe some of the
mechanisms of action of thalidomide, its collateral effects,
and some of its pharmacodynamical properties. We also discuss
the applications of the drug in various diseases, and especially
in leprosy and multiple myeloma, on the basis of an extensive
review of the literature.
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Thalidomide and Analogs as Anti-inflammatory and Immunomodulator
Drug Candidates
L.M. Lima, C.A.M. Fraga, V.L.G. Koatz and E.J. Barreiro
Thalidomide ([2-(2,6-dioxo-hexahydro-3-(R,S)-pyridinyl)-1,3-isoindolinedione]),
well known by its teratogenic effect, caused birth defects
in up to 12,000 children in the 1960s. More recently, this
drug was approved by the US Food and Drug Administration for
the treatment of erythema nodosum leprosum, under restricted-use
program, and a variety of new possible therapeutic applications
have been described. This article will accomplish a review
of medicinal chemistry aspects of thalidomide and state of
the art in the development of new anti-inflammatory and immunomodulator
drug candidates designed using thalidomide as lead-compound.
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