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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 23, 2007
Contents
The “Parkinsonian Heart”: From Novel Vistas to
Advanced Therapeutic Approaches in Parkinson’s Disease
Pp. 2421-2428
Francesco Fornai, Riccardo Ruffoli, Paola Soldani, Stefano
Ruggieri and Antonio Paparelli
[Abstract]
P2Y Receptors: Focus on Structural, Pharmacological
and Functional Aspects in the Brain Pp. 2429-2455
W. Fischer and U. Krügel
[Abstract]
The Many Roles of Chemokine Receptors in Neurodegenerative
Disorders: Emerging New Therapeutical Strategies
Pp. 2456-2470
Marjelo Mines, Yun Ding and Guo-Huang Fan
[Abstract]
The Discovery of the Factor Xa Inhibitor Otamixaban:
From Lead Identification to Clinical Development
Pp. 2471-2481
Kevin R. Guertin and Yong-Mi Choi
[Abstract]
Tight Junction Modulators: Promising Candidates for
Drug Delivery Pp. 2482-2488
M. Kondoh and K. Yagi
[Abstract]
Onconeural Versus Paraneoplastic Antigens?
Pp. 2489-2494
S.B. Eichmüller and A.V. Bazhin
[Abstract]
Antiangiogenic Agents: an Update on Small Molecule
VEGFR Inhibitors Pp. 2495-2516
S. Schenone, F. Bondavalli and M. Botta
[Abstract]
The DDX3 Subfamily of the DEAD Box Helicases: Divergent
Roles as Unveiled by Studying Different Organisms and In
Vitro Assays Pp. 2517-2525
A. Rosner and B. Rinkevich
[Abstract]
Abstracts
[Back to top]
The “Parkinsonian Heart”: From
Novel Vistas to Advanced Therapeutic Approaches in Parkinson’s
Disease
Francesco Fornai, Riccardo Ruffoli, Paola Soldani, Stefano
Ruggieri and Antonio Paparelli
The present manuscript reviews novel data on the progressive
involvement of different regions of the central nervous system
as well as peripheral nerves in Parkinson’s disease.
Most of these regions are involved in the regulation of the
autonomic nervous system, and their damage is concomitant
with the specific loss of sympathetic cardiac axon terminals.
This causes a cardiovascular dysfunction, which occurs solely
in Parkinsonian patients. In order to specify the peculiarity
of this cardiovascular alteration we coined the term “Parkinsonian
Heart”. This is characterized by a severe loss of the
physiological noradrenergic innervation and a slight impairment
of central autonomic control and it is often characterized
by drug-induced morpho-functional alterations. In fact, the
current dopamine sub-stitution therapy could make worse such
an already abnormal heart. For instance, structure-activity
studies on dopamine substitutive drugs report that dopamine
agonists belonging to the class of ergot derivatives may produce,
with a high frequency, valvular fibrosis in Parkinsonian patients.
These effects recently became a major issue and led to consider
all ergot dopamine agonists as dangerous for the treatment
of Parkinson’s disease. In the present review we re-describe
the effects of dopamine agonist within the specific context
of the Parkinsonian heart. In line with this, additional factors
need to be considered: 1- The lack of noradrenergic innervation
which might play a significant role in the fibrogenic mechanism.
2- The ergot structure per se, which is not sufficient,
but it is rather the ability to act as agonist at 5HT2B
or alpha-noradrenergic receptors to determine the fibrotic
reaction. Therefore, we suggest that binding to these receptor
subtypes, joined with the lack of endogenous noradrenergic
innervation, might synergize to produce the cardiac fibrosis.
[Back to top]
P2Y Receptors: Focus on Structural, Pharmacological
and Functional Aspects in the Brain
W. Fischer and U. Krügel
Purine and pyrimidine nucleotides have been identified as
potent extracellular signalling molecules, acting at two classes
of cell surface receptors, ionotropic P2X and metabotropic
P2Y receptor (-R) types. Hitherto eight subtypes of the P2Y-R
family have been cloned from mammalian species that exhibit
sensitivity to the adenine nucleotides ATP/ADP (P2Y1,11,12,13),
the uracil nucleotides UTP/UDP (P2Y2,4,6
or UDP-glucose in the case of P2Y14)
or both adenine and uracil nucleotides (P2Y2).
The P2Y-Rs are G protein-coupled receptors activating phospholipase
C via Gαq/11
protein and stimulating or inhibiting adenylyl cyclase via
Gαs
and Gαi/o
proteins, respectively. These receptors may activate distinct
signalling cascades. Although classical models predict that
P2Y-Rs exist in the cell membrane as monomers, homo- or heterodimeric
assemblies may be generated. Interactions with certain ion
channels or ligand-gated receptors as well as the co-localization
of several receptor subtypes in the same cell provide the
basis for a high functional diversity. The proteins for various
P2Y-Rs are expressed early in the embryonic brain and are
broadly distributed on both, neurons and astroglial cells.
P2Y-R involvement in the regulation of normal physiological
processes on the cellular level or in vivo, such
as modulation of transmitter release, generation of astroglial
Ca2+ waves, in diverse effects
on behavioural functions and in the etiopathology of neurodegenerative
diseases, are discussed and own data are presented. However,
the exact understanding of the role of individual P2Y-R subtypes
is still limited. Concerning the potentially important functions
of P2Y-Rs, there is a strong need to develop stable, lipophilic
and subtype-selective P2Y-R ligands, which may open new therapeutic
strategies.
[Back to top]
The Many Roles of Chemokine Receptors in Neurodegenerative
Disorders: Emerging New Therapeutical Strategies
Marjelo Mines, Yun Ding and Guo-Huang Fan
Chemokines and chemokine receptors, primarily found to play
a role in leukocyte migration to the inflammatory sites or
to second lymphoid organs, have recently been found expressed
on the resident cells of the central nervous system (CNS).
These proteins are important for the development of the CNS
and are involved in normal brain functions such as synaptic
transmission. Increasing lines of evidence have implicated
an involvement for chemokines and their receptors in several
neurodegenerative disorders, including Alzheimer’s disease
(AD), Parkinson’s disease (PD), human immunodeficiency
virus-associated dementia (HAD), multiple sclerosis (MS),
and stroke. Specific inhibition of the biological activities
of chemokine receptors could gain therapeutic benefit for
these neurodegenerative disorders. In recent years, non-peptide
antagonists of chemokine receptors have been disclosed and
tested in relevant pharmacological models and some of these
inhibitors have entered clinical trials. The aim of this review
is to outline the recent progress regarding the role of chemokines
and their receptors in neurodegenerative diseases and the
advancements in the development of chemokine receptor inhibitors
as potential therapeutic approaches for these neurodegenerative
diseases.
[Back to top]
The Discovery of the Factor Xa Inhibitor Otamixaban:
From Lead Identification to Clinical Development
Kevin R. Guertin and Yong-Mi Choi
Factor Xa (fXa) is a critical serine protease situated at
the confluence of the intrinsic and extrinsic pathways of
the blood coagulation cascade. FXa catalyses the conversion
of prothrombin to thrombin via the prothrombinase complex.
Its singular role in thrombin generation, coupled with its
potentiating effects on clot formation render it an attractive
target for therapeutic intervention.
Otamixaban is a synthetically derived parenteral fXa inhibitor
currently in late stage clinical development at Sanofi-Aventis
for the management of acute coronary syndrome. Otamixaban
is a potent (Ki = 0.5 nM), selective, rapid acting, competitive
and reversible fXa inhibitor that effectively inhibits both
free and prothrombinase-bound fXa. In vivo experiments
have demonstrated that Otamixaban is highly efficacious in
rodent, canine and porcine models of thrombosis. In addition,
recent clinical findings indicate that Otamixaban is efficacious,
safe and well tolerated in humans and therefore has considerable
potential for the treatment of acute coronary syndrome. This
review article chronicles the discovery and pre-clinical data
surrounding the fXa inhibitor Otamixaban as well as the recent
clinical findings in humans.
[Back to top]
Tight Junction Modulators: Promising Candidates for
Drug Delivery
M. Kondoh and K. Yagi
Recent advances in genomic drug development and high-throughput
technologies, such as combinatorial chemistry, high throughput
screening and in silico screening, are making it
easier to screen compounds with pharmaceutical activity. Drugs
developed by genomic and throughput technologies traverse
the epithelial and endothelial membranes. Although the paracellular
pathway is a potent drug delivery route for these drugs, few
strategies for their delivery have been developed because
tight junctions (TJs), which exist between adjacent cells,
strictly regulate the movement of solutes. Recent progress
in biology of TJs has provided new insights into the bio-chemical
and functional structure of TJs, and into the roles that occludin,
claudins and tricellulin play in regulating TJ barriers. Novel
strategies based on TJ-components for delivering drugs through
the paracellular pathway have been developed. In this review,
we discuss drug delivery through the paracellular route within
the context of biology of TJs, as well as future directions
of TJ-component-based drug delivery systems.
[Back to top]
Onconeural Versus Paraneoplastic Antigens?
S.B. Eichmüller and A.V. Bazhin
A hallmark of naturally occurring tumor immunity is the aberrant
expression of so called “onconeural antigens”
or “paraneoplastic antigens”. At present, these
two terms are used as synonyms for proteins which are normally
expressed only in neuronal tissues, but in the process of
carcinogenesis, they can be detected in tumors located outside
the nervous system. As neuronal tissues are immunopriveleged
zones, expression of these proteins in tumor cells can induce
an autoimmune response, which manifests in the generation
of autoantibodies and/or specific cytotoxic T-cells. Whether
or not such immune responses necessarily lead to paraneoplastic
syndromes or to a beneficial antitumor response or both is
not fully understood. In this review we comprehensively summarize
recent literature on paraneoplastic antigens including the
corresponding neurological syndromes. A unified classification
is proposed with “onconeural antigens” as collective
term and a number of subgroups including the recently discovered
cancer-retina antigens. Certain onconeural antigens can serve
as paraneoplastic antigens under conditions which have yet
to be defined, implying that the paraneoplastic function is
not inherent to the antigen. The potential of onconeural antigens
in cancer diagnostics and treatment strategies is discussed.
[Back to top]
Antiangiogenic Agents: an Update on Small Molecule
VEGFR Inhibitors
S. Schenone, F. Bondavalli and M. Botta
Angiogenesis is a tightly regulated process that leads to
the formation of new blood vessels sprouting from pre-existing
microvasculature and occurs in limited physiological conditions
or under pathological situations such as retinopathies, arthritis,
endometriosis and cancer. Blockade of angiogenesis is an attractive
approach for the treatment of such diseases. Particularly
in malignancies, antiangiogenic therapy should be less toxic
in comparison with conventional treatments such as chemotherapy,
as angiogenesis is a process relatively restricted to the
growing tumor. Vascular endothelial growth factor (VEGF) is
one of the most important inducers of angiogenesis and exerts
its cellular effects mainly by interacting with two high-affinity
transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and
VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of
VEGF receptor activity reduces angiogenesis. For these reasons,
the inhibition of VEGF or its receptor signalling system is
an attractive target for therapeutic intervention. The most
studied and developed inhibitors are monoclonal antibodies
that neutralize VEGF, ribozymes, and small molecule VEGFR
kinase inhibitors. Many important reviews dealing with VEGF-induced
angiogenesis and its inhibition through the block of VEGF
receptors have been reported, especially from a biological
point of view. Here, we will review small synthetic VEGFR
inhibitors that have appeared in literature in the last few
years, focusing our attention on their medicinal chemistry
in terms of chemical structure, mechanisms of action and structure-activity
relationships. In fact, there have been an increased number
of tyrosine kinase inhibitors in the most recent literature
reports; their biological profile is extremely interesting
and could be of great importance to medicinal chemists working
in this area in improving their efficacy.
[Back to top]
The DDX3 Subfamily of the DEAD Box Helicases: Divergent
Roles as Unveiled by Studying Different Organisms and In
Vitro Assays
A. Rosner and B. Rinkevich
DDX3 (or Ded1p), the highly conserved subfamily of the DEAD-box
RNA helicase family (40 members in humans), plays important
roles in RNA metabolism. DDX3X and DDX3Y, the two human paralogous
genes of this subfamily of proteins, have orthologous candidates
in a diverse range of eukaryotes, from yeast and plants to
animals. While DDX3Y, which is essential for normal spermatogenesis,
is translated only in the testes, DDX3X protein is ubiquitously
expressed, involved in RNA transcription, RNA splicing, mRNA
transport, translation initiation and cell cycle regulation.
Studies of recent years have revealed that DDX3X participates
in HIV and hepatitis C viral infections, and in hepatocellular
carcinoma, a complication of hepatitis B and hepatitis C infections.
In the urochordates (i.e., Botryllus schlosseri)
and in diverse invertebrate phyla (represented by model organisms
such as: Drosophila, Hydra, Planaria), DDX3 proteins
(termed also PL10) are involved in developmental pathways,
highly expressed in adult undifferentiated soma and germ cells
and in some adult and embryo's differentiating tissues. As
the mechanistic and functional knowledge of DDX3 proteins
is limited, we suggest assembling the available data on DDX3
proteins, from all studied organisms and in vitro
assays, depicting a unified mechanistic scheme for DDX3 proteins’
functions. Understanding the diverse functions of DDX3 in
multicellular organisms may be particularly important for
effective strategies of drug design.
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