| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 18, Number 10, 2011
Hot Topic
Non-Invasive Assessment of Asthmatic
Inflammation: From Bench to Bedside
Guest Editor: S. Loukides, K. Kostikas and P. Bakakos
Contents
Editorial: Pp. 1413-1414
Induced Sputum in Asthma: From Bench to Bedside Pp.
1415-1422
P. Bakakos, F. Schleich, M. Alchanatis and
R. Louis
[Abstract] [Purchase Article]
Exhaled Nitric Oxide in Asthma in Adults: The
End is the Beginning? Pp. 1423-1431
K. Kostikas, M. Minas, A.I. Papaioannou, S. Papiris and
R.A. Dweik
[Abstract] [Purchase Article]
Exhaled Breath Condensate in Asthma: From Bench
to Bedside Pp. 1432-1443
S. Loukides, K. Kontogianni, G. Hillas and I.
Horvath
[Abstract] [Purchase Article]
General Articles
The Importance of Alkynyl Chain Presence for the Activity
of Adenine Nucleosides/Nucleotides on Purinergic Receptors
Pp. 1444-1463
D. Dal Ben, M. Buccioni, C. Lambertucci, G. Marucci, R.
Volpini and G. Cristalli
[Abstract] [Purchase Article]
Hybrid Molecules Incorporating Natural Products:
Applications in Cancer Therapy, Neurodegenerative Disorders
and Beyond Pp. 1464-1475
M. Decker
[Abstract] [Purchase Article]
The Role of Cytokines in Atopic Asthma
Pp. 1476-1487
M. Finiasz, C. Otero, L. Bezrodnik and S. Fink
[Abstract] [Purchase Article]
Quinoline as a Privileged Scaffold in Cancer Drug
Discovery Pp. 1488-1508
V.R. Solomon and H. Lee
[Abstract] [Purchase Article]
Exploring Old Drugs for the Treatment of Hematological
Malignancies Pp. 1509-1514
F. Gan, B. Cao, D. Wu, Z. Chen, T. Hou and X.
Mao
[Abstract] [Purchase Article]
Oxysterol Derivatives of Cholesterol in Neurodegenerative
Disorders Pp. 1515-1525
T.M. Jeitner, I. Voloshyna and A.B. Reiss
[Abstract] [Purchase Article]
Pharmacophore Design of p38α
MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted
or 1,2,4,5-Tetrasubstituted Imidazole Scaffold Pp.
1526-1539
T. Scior, D.M. Domeyer, K. Cuanalo-Contreras
and S.A. Laufer
[Abstract] [Purchase Article]
Enlarging the NSAIDs Family: Ether, Ester and
Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel
Anti-Inflammatory and Analgesic Agents Pp. 1540-1554
M. Biava, G.C. Porretta, G. Poce, C. Battilocchio,
M. Botta, F. Manetti, M. Rovini, A. Cappelli, L. Sautebin,
A. Rossi, C. Pergola, C. Ghelardini, N. Galeotti, F. Makovec,
A. Giordani, P. Anzellotti, S. Tacconelli, P. Patrignani and
M. Anzini
[Abstract] [Purchase Article]
Falcipains, Plasmodium falciparum Cysteine Proteases
as Key Drug Targets Against Malaria Pp. 1555-1572
C. Teixeira, J.R.B. Gomes and P. Gomes
[Abstract] [Purchase Article]
Abstracts
[Back to top]
EDITORIAL: Non-Invasive Assessment of Asthmatic Inflammation:
From Bench to Bedside
Asthma is now recognized as a heterogeneous disease, based
on clinical parameters, the type of inflammation, the response
to treatment, the rate of exacerbations and, finally, the
underlying control and/or severity. Attempts to apply the
above diverse characteristics to the clinical presentation
of the disease have led to the identification of different
phenotypes, with significant overlapping. The field of non
invasive tech-niques has been rapidly developed since the
time that the fraction of exhaled nitric oxide (FeNO) was
recognized as an easily measured mediator in the exhaled air
[1]. At approximately the same time, induced sputum was recognized
as a valuable technique for the identification of the inflammatory
cellular population as well as for the evaluation of different
mediators in sputum supernatants [2]. Exhaled breath condensate
(EBC), a totally non invasive technique, gave us the opportunity
to sample the airways in an even more easily applicable approach,
but the several methodological pitfalls of this method prevent
it from being an accurate procedure for the evaluation of
airways inflammation [3]. The attempt to connect the whole
asthma entity and its numerous phenotypes using those minimally
invasive techniques, i.e. FeNO, induced sputum and EBC, involves
two major steps: First, these techniques must become more
widely accepted and applied and, second, we need data from
large multicenter studies that will identify the distinct
inflammatory characteristics of specific phenotypes.
Every single biomarker obtained by non invasive techniques
must fulfill some requirements, in order to be applicable
in every day clinical practice: it must be measurable in the
field, be measurable in the specific disease, have a standardized
methodology, have normal values that clearly discriminate
normality from disease, present reproducibility and stability
within measurements, be associated with an established in-flammatory
process and, finally, be applicable as a tool for guided treatment
strategy. According to these requirements, it is quite difficult
or even impossible for a single biomarker obtained from non
invasive techniques to fulfill them.
The majority of the numerous studies involving non invasive
techniques for the assessment of airways inflammation evaluated
the discri-minative power of biomarkers in respect to the
presence or absence of a specific disease. This approach has
certain value, but does not add useful information for clinical
practice in an inflammatory disease that presents significant
day-to-day variability such as asthma. A more useful approach
would be to evaluate a specific biomarker using statistical
tools dedicated to test the diagnostic performance of a biomarker.
For example, using receiver operating characteristics (ROC)
analysis we can define specific cut-off values that may characterize
the potential utility of a biomarker as a predictive tool
for survival or disease progression or even as a tool for
the prediction of other significant outcomes related to treatment
response. There is additional need for the validation of such
cut-off points in prospective trials involving decision-making.
The current literature presents only limited data in that
direction at the moment. The most promising data to-date are
those published for induced sputum, that have used a specific
cut-off value for eosinophils as predictors of severe exacerbations
in respect to treatment intervention with inhaled steroids
[4]. Similar data exist for FeNO in predicting multiple outcomes
in asthma, both clinical and/or inflammatory [5]. The majority
of the later studies have focused on sputum cellular population,
and particularly on eosinophils. In contrast to those two
widely evaluated biomarkers, the literature on EBC still does
not include any data for the support of the aforementioned
requirements. EBC pH is nowadays considered a promising parameter,
since its values may discriminate between asthmatics and normal
subjects [6] and present an association with eosinophilic
inflammation [7], but the absence of robust longitudinal data
still limits its application in clinical practice. Recently
published data in a prospective study showed that EBC pH can
be used to monitor asthma exacerbations, however with no associations
with alterations in lung function or FeNO [8].
In this hot topic issue, the three most widespread techniques
of non invasive or minimally invasive assessment of airways
inflammation are described in details, all the way from the
point of technical considerations to the implementation in
clinical practice. It is widely accepted that all these techniques
have provided clinicians and researchers with tools for the
understanding of the underlying pathophysiology of the disease.
But is this the main target? Definitely not. What we really
need from non invasive techniques is to be implemented in
clinical practice and provide useful information for the diagnostic
approach, the identification of specific phenotypes, the evaluation
of asthma control and the facilitation of decision-making.
FeNO represents the only exhaled asthma biomarker that has
reached clinical practice today. Despite some methodological
issues, FeNO represents a good surrogate biomarker of eosinophilic
airways inflammation, can serve as an aid to the diagnosis
of asthma, may identify loss or restoration of asthma control
as well as certain clinically relevant phenotypes (including
an "at risk" phenotype in severe asthma), may predict
steroid response and exacerbations, and may provide a possible
aid for treatment guidance, especially in patients with difficult
asthma [1]. Which is the contribution of EBC in the above
requirements? Although promising, EBC is currently used only
as a research tool, due to the lack of appropriate standardization
and the absence of reference values [9]. Some of the biomarkers
obtained by EBC can identify certain phenotypes, but with
significant overlapping between measurements. Last but not
least, sputum induction may share with FeNO some clinically
useful applications mainly related to the detection of non-adherence
to corticosteroid therapy, the assessment of the adequacy
of inhaled corticosteroid therapy, the long-term management
of asthma and the adjustment of oral corticosteroid dose in
refractory asthma. Specifically, induced sputum may be used
to study the dose-response effect of inhaled corticosteroids
and may be useful to establish the relative potency of different
corticosteroid formulations and delivery devices. Finally,
prospective studies have shown that it is better than clinical
assessment in reducing the rate of exacerbations [2], especially
the eosinophilic ones [10].
What do we expect from the biomarkers obtained by non invasive
methods in asthma? Based on the heterogeneity of the disease,
the need for identification of the different disease phenotypes
within the range of these syndromes is crucial for the proper
management of the individual patient. Based on current knowledge,
it is not likely that a single biomarker will suffice for
the identification of the underlying pathophysiology and/or
the clinically useful phenotyping of asthma. What is definitely
needed is the proper combination of biomarkers, even from
different techniques, in order to achieve their maximal effectiveness.
Clinical assessment and physiologic parameters, such as spirometry,
provide highly useful information, but they can not provide
objective information in relation to the inflammatory process.
The quest for a non invasive inflammometer has been a target
for both clinicians and researchers in the past twenty years.
Considering that the term inflammation is highly heterogeneous,
we should be definitely seeking ways to combine the inflammatory
characteristics with clinical features in order to characterize
particular phenotypes. This concept may help physicians provide
individualized treatment for each patient in the future.
REFERENCES
[1] Barnes, P.J.; Dweik, R.A.; Gelb, A.F.; Gibson, P.G.; George,
S.C.; Grasemann, H.; Pavord, I.D.; Ratjen, F.; Silkoff, P.E.;
Taylor, D.R.; Zamel, N. Exhaled nitric oxide in pulmonary
diseases: a comprehensive review. Chest, 2010,
138(3), 682-692.
[2] Brightling, C.E. Clinical applications of induced sputum.
Chest, 2006, 129(5), 1344-1348.
[3] Horvath, I.; Hunt, J.; Barnes, P.J.; Alving, K.; Antczak,
A.; Baraldi, E.; Becher, G.; van Beurden, W.J.; Corradi, M.;
Dekhuijzen, R.; Dweik, R.A.; Dwyer, T.; Effros, R.; Erzurum,
S.; Gaston, B.; Gessner, C.; Greening, A.; Ho, L.P.; Hohlfeld,
J.; Jobsis, Q.; Laskowski, D.; Loukides, S.; Marlin, D.; Montuschi,
P.; Olin, A.C.; Redington, A.E.; Reinhold, P.; van Rensen,
E.L.; Rubinstein, I.; Silkoff, P.; Toren, K.; Vass, G.; Vogelberg,
C.; Wirtz, H. Exhaled breath condensate: methodological recommendations
and unresolved questions. Eur. Respir. J., 2005,
26(3), 523-548.
[4] Green, R.H.; Brightling, C.E.; McKenna, S.; Hargadon,
B.; Parker, D.; Bradding, P.; Wardlaw, A.J.; Pavord, I.D.
Asthma exacerbations and sputum eosinophil counts: a randomised
controlled trial. Lancet, 2002,
360(9347), 1715-1721.
[5] Taylor, D.R. An eye to the future: exhaled nitric oxide
as a predictor of clinical outcomes in asthma. Eur. Respir.
J., 2010, 35(6), 1200-1202.
[6] Paget-Brown, A.O.; Ngamtrakulpanit, L.; Smith, A.; Bunyan,
D.; Hom, S.; Nguyen, A.; Hunt, J.F., Normative data for pH
of exhaled breath condensate. Chest, 2006,
129(2), 426-430.
[7] Kostikas, K.; Papatheodorou, G.; Ganas, K.; Psathakis,
K.; Panagou, P.; Loukides, S. pH in expired breath condensate
of patients with inflammatory airway diseases. Am. J.
Respir. Crit. Care Med., 2002, 165(10),
1364-1370.
[8] Antus, B.; Barta, I.; Kullmann, T.; Lazar, Z.; Valyon,
M.; Horvath, I.; Csiszer, E. Assessment of exhaled breath
condensate pH in exacerbations of asthma and chronic obstructive
pulmonary disease: A longitudinal study. Am. J. Respir.
Crit. Care Med., 2010, 182(12),
1492-1497.
[9] Koutsokera, A.; Loukides, S.; Gourgoulianis, K.I.; Kostikas,
K. Biomarkers in the exhaled breath condensate of healthy
adults: mapping the path towards reference values. Curr.
Med. Chem., 2008, 15(6), 620-630.
[10] Jayaram, L.; Pizzichini, M.M.; Cook, R.J.; Boulet, L.P.;
Lemiere, C.; Pizzichini, E.; Cartier, A.; Hussack, P.; Goldsmith,
C.H.; Laviolette, M.; Parameswaran, K.; Hargreave, F.E. Determining
asthma treatment by monitoring sputum cell counts: effect
on exacerbations. Eur. Respir. J., 2006,
27(3), 483-494.
Stelios Loukides
2nd Respiratory Medicine
Department
University of Athens Medical School
Smolika 2 16673 Athens
Greece
Tel: +306944380549
Fax: +302107770423
E-mail: ssat@hol.gr
Konstantinos Kostikas
2nd Respiratory Medicine
Department
University of Athens Medical School
Athens
Greece
Tel: +306944780616
Fax: +302441022370
E-mail: ktk@otenet.gr
Petros Bakakos
1st Respiratory Medicine
Department
University of Athens Medical School
Athens
Greece
Tel: +306974748113
Fax: +302107770423
E-mail: petros44@hotmail.com
[Back to top] [Purchase Article]
Induced Sputum in Asthma: From Bench to Bedside
P. Bakakos, F. Schleich, M. Alchanatis and
R. Louis
During recent years there has been a growing interest
in using non-invasive biomarkers to understand and monitor
the airway inflammation in subjects with respiratory tract
disorders and mainly asthma and chronic obstructive pulmonary
disease (COPD). Sputum induction is generally a well-tolerated
and safe procedure and a European Respiratory Society Task
Force has published a comprehensive review on sputum methodology.
Induced sputum cell count and, to a lesser extent, mediator
measurements have been particularly well validated. In asthma,
the sputum and the cell culture supernatant can be used for
the measurement of a variety of soluble mediators, including
eosinophil-derived proteins, nitric oxide (NO) derivatives,
cytokines and remodelling-associated proteins. Sputum eosinophilia
(> 3%) is a classic feature of asthma although half of
the patients seems to be non eosinophilic. Measuring the percentage
of sputum eosinophils has proved to be useful in the clinical
arena in helping to predict short term response to inhaled
corticosteroids (ICS) and tailor the dose of ICS in the severe
patients but there is scope for the application of other induced
sputum markers potentially useful in clinical practice. The
widespread application of induced sputum in asthma across
the spectrum of disease severity has given insight into the
relationship between airway function and airway inflammation,
proposed new disease phenotypes and defined which of these
phenotypes respond to current therapy, and perhaps most importantly
provided an additional tool to guide the clinical management
of asthmatic patients. To date sputum induction is the only
non-invasive measure of airway inflammation that has a clearly
proven role in asthma management.
[Back to top] [Purchase Article]
Exhaled Nitric Oxide in Asthma in Adults: The
End is the Beginning?
K. Kostikas, M. Minas, A.I. Papaioannou, S. Papiris and
R.A. Dweik
Approximately 20 years after the initial report of the
measurement of exhaled nitric oxide (NO) in the exhaled air
of humans, numerous publications have evaluated the possible
applications of the fraction of exhaled NO (FeNO) in patients
with asthma. The aim of the present review is to evaluate
the technical issues and confounding factors related to FeNO
measurements, as well as the role of FeNO in the diagnosis
of asthma, the evaluation of asthmatic patients and the guidance
of treatment. Several other issues, including the pursuit
for "normal" and best personal values, the prediction
of clinically relevant asthma outcomes and the identification
of asthma phenotypes and future directions are discussed.
FeNO represents the only exhaled biomarker that has reached
clinical practice even in primary care settings and this review
provides a critical view of the possible applications of this
biomarker, both for the basic researcher and the clinician.
[Back to top] [Purchase Article]
Exhaled Breath Condensate in Asthma: From Bench
to Bedside
S. Loukides, K. Kontogianni, G. Hillas and I.
Horvath
The need for non-invasive assessment of airway inflammation
is imperative, since inflammatory airway diseases, such as
asthma and COPD, are characterized by variation in their clinical
presentation throughout their course. Exhaled breath condensate
(EBC) collection represents a rather appealing method that
can be used to conveniently and noninvasively collect a wide
range of volatile and non-volatile molecules from the respiratory
tract, without affecting airway function or inflammation.
Although promising, EBC is currently used only as a research
tool, due to the lack of appropriate standardization and the
absence of reference values. A large number of mediators of
inflammation, oxidative and nitrosative stress, including
adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes,
prostanoids, nitrogen oxides, peptides and cytokines, have
been studied in EBC. This review focuses mainly on the presentation
of the above biomarkers in asthma as well as on the effect
of various factors on their concentrations. Concentrations
of such mediators have been shown to be related to the underlying
asthma and its severity and to be modulated by therapeutic
interventions. Despite the encouraging positive results up-to-date,
the introduction of EBC in everyday clinical practice requires
the work-out of some methodological pitfalls, the standardization
of EBC collection, and finally the identification of a reliable
biomarker which is reproducible, has normal values and provides
information for the underlying inflammatory process and the
response to treatment. So far none of the parameters studied
in EBC fulfils the aforementioned requirements.
[Back to top] [Purchase Article]
The Importance of Alkynyl Chain Presence for the
Activity of Adenine Nucleosides/Nucleotides on Purinergic
Receptors
D. Dal Ben, M. Buccioni, C. Lambertucci, G. Marucci, R.
Volpini and G. Cristalli
The first demonstrations in the early seventies that adenosine
had marked effects in the cerebral cortex, which were independent
of its role in intermediary metabolism and could be antagonised
by methylxanthines, were followed by the observations that
other purine derivatives, notably ATP, may also play a critical
role in cell function. In 1978 Burnstock first introduced
the terms Pl for the nucleoside receptors and P2 for the nucleotide
receptors, based on the most fundamental divisions of purine
receptors between those for nucleosides such as adenosine
and those for nucleotides such as ATP. At present, the P1
(adenosine) receptor family presents 4 subtypes, while the
P2 (ATP, ADP and UTP) receptor family has been divided into
P2X ionotropic receptors and P2Y metabotropic G protein-coupled
receptors (GPCRs). While knowledge on the purinergic receptor
pharmacology was increasing, the development of potent and
selective ligands for these receptors has been a target of
medicinal chemistry research for several decades. In particular,
synthesis of 2-substituted adenosines was carried out in many
laboratories starting from seventies aimed at finding adenosine
derivatives more resistant than the parent nucleoside to rapid
uptake into cells, to deamination by adenosine deaminase,
and to phosphorylation by adenosine kinase. In the present
review the synthesis of alkynyl derivatives of adenine, adenosine,
N-alkylcarboxamidoadenosine, and adenine nucleotides, which
have been tested on purinergic receptors, will be summarized.
Furthermore, the contribution of chemistry, molecular modelling,
and pharmacology to the development of structure-activity
relationships in this class of purinergic receptor ligands
will be outlined.
[Back to top] [Purchase Article]
Hybrid Molecules Incorporating Natural Products:
Applications in Cancer Therapy, Neurodegenerative Disorders
and Beyond
M. Decker
In this article the design of hybrid molecules that covalently
connect two distinct drug entities in one molecule, at least
one part being a biologically active natural product will
be discussed. In the quest for novel drug entities, the hybrid
approach is a promising path to drug molecules that can effectively
target multifactorial diseases including neurodegenerative
disorders like Alzheimer’s and Parkinson’s diseases
(AD and PD). The hybrid approach can also be used to optimize
certain biological properties like affinity and selectivity,
but also to gain novel biological activities distinct from
the ones of the components.
Due to the high potential of natural products to exhibit pronounced
biological activities, natural products have been one of the
major sources of components in hybrid molecules. This review
will cover their applications in developing drugs for neurodegenerative
disorders, in the diverse field of anti-cancer agents (which
represents the major application for natural products in medicinal
chemistry), but also in miscellaneous areas of bioactive compounds
including antioxidants, antimalarial drugs and estrogen-related
hybrids to reach various therapeutic aims.
The unique tasks of hybrid molecule design will be addressed,
such as describing suitable ways to chemically connect the
drug components, how to use the approach to enhance biological
activity with respect to both activity and selectivity and
potential drawbacks of the hybrid approach. It will be shown
that hybrids can be more than the sum of their components,
but in many cases should be considered as pharmacological
entities in their own respect.
[Back to top] [Purchase Article]
The Role of Cytokines in Atopic Asthma
M. Finiasz, C. Otero, L. Bezrodnik and S. Fink
Atopic asthma results from airway inflammation triggered
by an environmental allergen. Symptoms include wheezing, dyspnea
and cough, airway narrowing and/or hyperresponsiveness to
several inhaled stimuli. Inflammation develops in a two-phase
fashion. The first phase after exposure to the allergen consists
of degranulation and release of both histamine and other stored
preformed inflammatory mediators as well as newly synthesized
ones, including cytokines, all of which increase mucus secretion
and smooth muscle contraction. The second phase occurs later
and lasts longer; it is due to different molecules: several
cytokines and chemokines, arachidonic acid derivatives, enzymes
such as metalloproteinases and cell adhesion molecules. Cytokines
are key players in the chronic inflammation in asthma patients,
but details on their role and interactions still remain undetermined.
Recent evidence suggests that allergic asthma is a multifaceted
condition actively controlled by effector as well as regulatory
T cells (Tregs). T helper (Th) 2 cells and Th17 cells increase
airway inflammation, while Tregs are anti- inflammatory. Cytokines
are involved in the development and activation of all T cell
subpopulations. They are also involved directly or indirectly
in most approaches to asthma treatment. Several cytokines
have been tested as therapeutic targets and some of the currently
used therapies like corticosteroids, beta agonists and allergen
immunotherapy affect cytokine production. The increased knowledge
on cytokine interplay and lymphocyte subsets should generate
new therapeutic strategies in the near future.
[Back to top] [Purchase Article]
Quinoline as a Privileged Scaffold in Cancer Drug
Discovery
V.R. Solomon and H. Lee
Quinoline (1-azanaphthalene) is a heterocyclic aromatic
nitrogen compound characterized by a double-ring structure
that contains a benzene ring fused to pyridine at two adjacent
carbon atoms. Quinoline compounds are widely used as “parental”
compounds to synthesize molecules with medical benefits, especially
with anti-malarial and anti-microbial activities. Certain
quinoline-based compounds also show effective anticancer activity.
This broad spectrum of biological and biochemical activities
has been further facilitated by the synthetic versatility
of quinoline, which allows the generation of a large number
of structurally diverse derivatives. This includes numerous
analogues derived from substitution of the quinoline ring
system, and derivatization of quinoline ring structure. Quinoline
and its analogs have recently been examined for their modes
of function in the inhibition of tyrosine kinases, proteasome,
tubulin polymerization and DNA repair. In this review, we
have summarized our knowledge on quinoline compounds with
respect to their anticancer activities, mechanisms of action,
structure-activity relationship (SAR), and selective and specific
activity against various cancer drug targets. In particular,
we focus our review on in vitro and in vivo
anticancer activities of quinoline and its analogs in the
context of cancer drug development and refinement.
[Back to top] [Purchase Article]
Exploring Old Drugs for the Treatment of Hematological
Malignancies
F. Gan, B. Cao, D. Wu, Z. Chen, T. Hou and X.
Mao
Drug discovery is costly and time-consuming, but it will
become easier and simpler if a drug could be developed from
an old one with well-documented investigations associated
with pharmacology, pharmacokinetics, toxicology and clinical
safety. In terms of hematological malignancies, several successful
drugs have been discovered and developed from old ones such
as arsenic trioxide for acute promyelocytic leukemia and thalidomide
for multiple myeloma. In this review, we discussed the latest
advancement in exploring old drugs for the treatment of hematological
malignancies.
[Back to top] [Purchase Article]
Oxysterol Derivatives of Cholesterol in Neurodegenerative
Disorders
T.M. Jeitner, I. Voloshyna and A.B. Reiss
Cholesterol is essential to the functions of the brain,
which contains approximately 20% of the body’s stores
of this sterol. Most brain cholesterol is found in compacted
myelin. The operation of the blood brain barrier (BBB) precludes
the uptake of cholesterol from the periphery and consequently
this sterol is produced de novo in the brain. In contrast,
oxysterols – a class of hydroxylated cholesterol catabolites
– traverse the BBB readily and facilitate the elimination
of cholesterol from the brain. Oxysterols not only act as
a transport form of cholesterol, but serve as endogenous regulators
of gene expression in lipid metabolism and behave as ligands
to nuclear receptors. Two of the more important brain-derived
oxysterols are 24S-hydroxycholesterol and 27-hydroxycholesterol.
Aberrant cholesterol metabolism has been implicated in a number
of neurological disorders. Since oxysterols are thought to
reflect the cerebral cholesterol turnover there has been great
interest in the diagnostic and prognostic value of these metabolites
in neurodegenerative diseases of the brain. The following
article provides an overview of the involvement of oxysterols
in Alzheimer’s disease, multiple sclerosis and spastic
paraplegias.
[Back to top] [Purchase Article]
Pharmacophore Design of p38α
MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted
or 1,2,4,5-Tetrasubstituted Imidazole Scaffold
T. Scior, D.M. Domeyer, K. Cuanalo-Contreras
and S.A. Laufer
Synthetic compounds with a tri- and tetra-substituted
imidazole scaffold are known as selective inhibitors of the
p38 mitogen-activated protein (MAP) kinase responsible for proinflammatory cytokine release. The scope is to review the
literature describing their design, synthesis and activity
studies. To date a great plethora of crystal structures of
p38 in complex with small organic ligands have been published. Cocrystallized ligand information is of particular interest
to our review study, i.e. ATP itself, the reference inhibitor
SB203580 with its aryl-pyridinyl-imidazoles and related imidazole
and pyrimidine-based derivatives. The selective inhibitors
bind to the pocket of adenosine 5'-triphoshate (ATP) replacing
the latter. The hydrophobic region II, however, is not occupied
by the natural binder ATP, but accommodates the pyridine substituents
preserving the 4-fluorophenyl ring occupation in pocket I
as a prerequisite to gain higher binding selectivity and potency
than the reference compound SB203580 (4-[5-(4-fluoro-phenyl)-2-(4-methanesulfinyl-phenyl)-3h imidazol-4-yl]-pyridine).
Experimental and computed work is reviewed which evidence that the 2 position of the pyrimidine ring is amenable to
the introduction of a side chain and the replacement of pyridine
in SB203580 by a pyrimidine ring improves both inhibitory
activity and selectivity for p38 over other kinases. All ligands
with a pyridyl C2 side chain occupy the hydrophobic pocket
II and in some cases a double hydrogen bond is reported between
methionine 109 and glycine 110 of the hinge region, following
an observed backbone shift. The substituted pyridine ring
binds stronger than the two other side chains on the imidazole
scaffold.
[Back to top] [Purchase Article]
Enlarging the NSAIDs Family: Ether, Ester and
Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel
Anti-Inflammatory and Analgesic Agents
M. Biava, G.C. Porretta, G. Poce, C. Battilocchio,
M. Botta, F. Manetti, M. Rovini, A. Cappelli, L. Sautebin,
A. Rossi, C. Pergola, C. Ghelardini, N. Galeotti, F. Makovec,
A. Giordani, P. Anzellotti, S. Tacconelli, P. Patrignani and
M. Anzini
The development of the coxib family has represented a stimulating
approach in the treatment of inflammatory disorders, such
as arthritis, and for the management of acute pains, in relation
to the well-known traditional Non-Steroidal Anti-inflammatory
Drugs (t-NSAIDs). Prompted by the pursuit for new cyclooxygenase-2
(COX-2) inhibitors, endowed with fine tuned selectivity and
high potency, in the past years we have identified novel classes
of ether, ester and acid molecules characterized by the 1,5-diarylpyrrole
scaffold as potentially powerful anti-inflammatory molecules
(12-66). All compounds proved to exert an
in vitro inhibition profile as good as that shown
by reference compounds. Compounds bearing a p-methylsulfonylphenyl
substituent at C5 displayed the best issues. In particular,
ester derivatives proved to perform the best in vitro
profile in terms of selectivity and activity toward COX-2.
The cell-based assay data showed that an increase of hindrance
at the C3 side chain of compounds could translate to activity
enhancement. The human whole blood (HWB) test let to highlight
that submitted compounds displayed 5-10 fold higher selectivity
for COX-2 vs COX-1 which should translate clinically to an
acceptable gastrointestinal safety and mitigate the cardiovascular
effects highlighted by highly selective COX-2 inhibitors.
Finally, to assess in vivo anti-inflammatory and analgesic
activity three different tests (rat paw pressure, rat paw
oedema and abdominal constriction) were performed. Results
showed good in vivo anti-inflammatory and analgesic
activities. The issues gained with these classes of compounds
represent, nowadays, a potent stimulus for a further enlargement
of the NSAIDs family. In this review we describe the results
obtained by our research group on this topic.
[Back to top] [Purchase Article]
Falcipains, Plasmodium falciparum Cysteine Proteases
as Key Drug Targets Against Malaria
C. Teixeira, J.R.B. Gomes and P. Gomes
There is a high demand for new drugs against malaria, which
takes millions of lives annually. The abuse of classical antimalarials
from the late 1940’s to the early 1980’s has bred
resistant parasites, which led to the use of more potent drugs
that ended up by refueling the resistance cycle. An example
is chloroquine, once highly effective but now virtually useless
against malaria.
Structure-based rational drug design relies on high-resolution
target structures to allow for screening of selective ligands/inhibitors.
For the past two decades, and especially after the unveiling
of the Plasmodium falciparum genome in 2002, enzymes of this
lethal malaria parasite species have been increasingly attracting
the attention of Medicinal Chemists worldwide as promising
drug targets. There is particular emphasis on proteases having
key roles on the degradation of host’s hemoglobin within
the food vacuole of blood-stage parasites, as these depend
on such process for their survival. Among such enzymes, Plasmepsins
(aspartic proteases) and, especially, Falcipains (cysteine
proteases) are highly promising antimalarial drug targets.
The present review will focus on the computational approaches
made so far towards the unraveling of the structure, function
and inhibition of Falcipains that, by virtue of their quite
specific features, are excellent targets for highly selective
inhibitors.
|
