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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 26, 2007
Contents
Inhibitors of HIV-1 Protease: Current State of the Art 10
Years After their Introduction. From Antiretroviral Drugs
to Antifungal, Antibacterial and Antitumor Agents Based on
Aspartic Protease Inhibitors Pp. 2734-2748
Antonio Mastrolorenzo, Stefano Rusconi, Andrea Scozzafava,
Giuseppe Barbaro and Claudiu T. Supuran
[Abstract]
Renin-Angiotensin System Inhibitors as Therapeutic
Alternatives in the Treatment of Chronic Liver Diseases
Pp. 2749-2754
Hitoshi Yoshiji, Ryuichi Noguchi, Yasuhide Ikenaka, Mitsuteru
Kitade, Kosuke Kaji, Tatsuhiro Tsujimoto, Masahito Uemura
and Hiroshi Fukui
[Abstract]
An Updated Unified Pharmacophore Model of the Benzodiazepine
Binding Site on γ-Aminobutyric
Acida Receptors: Correlation with Comparative Models
Pp. 2755-2775
T. Clayton, J.L. Chen, M. Ernst, L. Richter, B.A. Cromer,
C.J. Morton, H. Ng, C.C. Kaczorowski, F.J. Helmstetter, R.
Furtmüller, G. Ecker, M.W. Parker, W. Sieghart and J.M.
Cook
[Abstract]
Therapeutic Targets in Respiratory Viral Infections
Pp. 2776-2782
Gernot Rohde
[Abstract]
Interactions Between Growth Hormone and the Thyroid
Gland – with Special Reference to Biochemical Diagnosis
Pp. 2783-2788
Ulla Feldt-Rasmussen
[Abstract]
Computer Simulation of Antimicrobial Peptides
Pp. 2789-2798
Edit Mátyus, Christian Kandt and D. Peter Tieleman
[Abstract]
Valproate and Neuroendocrine Changes in Relation to
Women Treated for Epilepsy and Bipolar Disorder: A Review
Pp. 2799-2812
M.F. Reynolds, E.C. Sisk and N.L. Rasgon
[Abstract]
Application of the O–N Intramolecular Acyl Migration
Reaction in Medicinal Chemistry Pp. 2813-2823
Mariusz Skwarczynski and Yoshiaki Kiso
[Abstract]
Isoflavones, Equol and Cardiovascular Disease: Pharmacological
and Therapeutic Insights Pp. 2824-2838
Katherine A. Jackman, Owen L. Woodman and Christopher
G. Sobey
[Abstract]
Synthetic Peptides: The Future of Patient
Management in Systemic Rheumatic Diseases? Pp. 2831-2838
Kai Kessenbrock, Reinout Raijmakers, Marvin J. Fritzler
and Michael Mahler
[Abstract]
Abstracts
[Back to top]
Inhibitors of HIV-1 Protease: Current State of the Art 10
Years After their Introduction. From Antiretroviral Drugs
to Antifungal, Antibacterial and Antitumor Agents Based on
Aspartic Protease Inhibitors
Antonio Mastrolorenzo, Stefano Rusconi, Andrea Scozzafava,
Giuseppe Barbaro and Claudiu T. Supuran
The introduction of highly active antiretroviral therapy
(HAART) in 1996 dramatically changed the course of HIV infection.
This therapy involves the use of at least three agents from
two distinct classes of antivirals: a protease inhibitor (PI)
in combination with two nucleoside/nucleotide reverse transcriptase
inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase
inhibitor (NNRTI) in combination with NRTIs. Nine drugs containing
PIs are clinically available: the first generation ones, saquinavir,
ritonavir, indinavir, nelfinavir, and amprenavir, and the
second generation ones, fosamprenavir (the amprenavir prodrug),
lopinavir, atazanavir, and tipranavir. Many other compounds
are in advanced clinical evaluation, such as among others
TMC-114, whereas a lot of different other effective HIV protease
inhibitors were reported, mainly by using amprenavir and TMC-114
as lead molecules. The main goals of research in this field
are: (i) the design of better pharmacological agents, devoid
of severe side effects, resistance problems and with simple
administration schedules (preferably once daily), and (ii)
achieving eradication of the virus, and possibly, a definitive
cure of the disease. A review on the pharmacology and interactions
of these agents with other drugs is presented here, with emphasis
on how these pharmacological interferences may improve the
clinical use of antivirals, or how side effects due to PI
drugs may be managed better by taking them into account (such
as for example ritonavir boosting of other PIs which reduces
dosages and administration schedules of these drugs). Except
for being highly effective in the treatment of HIV infection,
recent reports showed this class of drugs to be effective
as antitumor agents, as antibacterials (for example against
Mycobacterium tuberculosis infection), antifungals
(against Candida albicans), antimalarials, antiSARS
and anti-influenza agents.
[Back to top]
Renin-Angiotensin System Inhibitors as Therapeutic
Alternatives in the Treatment of Chronic Liver Diseases
Hitoshi Yoshiji, Ryuichi Noguchi, Yasuhide Ikenaka, Mitsuteru
Kitade, Kosuke Kaji, Tatsuhiro Tsujimoto, Masahito Uemura
and Hiroshi Fukui
The renin-angiotensin system (RAS) is frequently activated
in the patients with chronic liver diseases, and recent studies
have shown that RAS plays a pivotal role in the progression
of chronic liver diseases, i.e., liver fibrosis and hepatocellular
carcinoma (HCC). Angiotensin-II (AT-II) reportedly stimulates
contractility and proliferation of the activated hepatic stellate
cells, and increases the transforming growth factor-β.
(TGF-β)
expression through angiotensin type-I receptors (AT1-R). Many
studies have demonstrated that the clinically used angiotensin-converting
enzyme inhibitors (ACE-I) and AT1-R blockers (ARB) significantly
attenuated the liver fibrosis development in the experimental
studies and clinical practice. AT-II also strongly promotes
neovascularization, which plays a pivotal role in tumor development.
AT-II induces a potent angiogenic factor; namely, the vascular
endothelial growth factor (VEGF). It has been reported that
ACE-I significantly attenuated the experimental HCC growth
and hepatocarcinogenesis along with suppression of neovascularization.
The VEGF expression in the tumor was suppressed by ACE-I,
too. The combined treatment of ACE-I with other clinically
used agents, such as interferon, imatinib mesylate, and vitamin
K, shows more potent inhibitory effects on the development
of liver fibrosis and HCC. Since RAS inhibitors are widely
used in the clinical practice without serious side effects,
they may represent a potential new therapeutic strategy against
the progression of chronic liver diseases.
[Back to top]
An Updated Unified Pharmacophore Model of the Benzodiazepine
Binding Site on γ-Aminobutyric
Acida Receptors: Correlation with Comparative Models
T. Clayton, J.L. Chen, M. Ernst, L. Richter, B.A. Cromer,
C.J. Morton, H. Ng, C.C. Kaczorowski, F.J. Helmstetter, R.
Furtmüller, G. Ecker, M.W. Parker, W. Sieghart and J.M.
Cook
A successful unified pharmacophore/receptor model which has
guided the synthesis of subtype selective compounds is reviewed
in light of recent developments both in ligand synthesis and
structural studies of the binding site itself. The evaluation
of experimental data in combination with a comparative model
of the αlβ2γ2
GABAA receptor leads to an
orientation of the pharmacophore model within the Bz BS. Results
not only are important for the rational design of selective
ligands, but also for the identification and evaluation of
possible roles which specific residues may have within the
benzodiazepine binding pocket.
[Back to top]
Therapeutic Targets in Respiratory Viral Infections
Gernot Rohde
Respiratory viral infections account for a substantial proportion
of morbidity world wide and contribute notably to the socio-economic
burden of diseases. Amongst the most important viruses identified
so far are Rhinoviruses, Influenza A and Respiratory Syncytial
Virus. The knowledge base has broadened at the clinical and
experimental level in recent years. However, therapeutic options
are still limited. This may be partly due to the multiplicity
of infectious mechanisms and the complex underlying host/virus
interactions. The aim of this article is to give an overview
of the different respiratory viruses involved, their major
principles of infection and the associated therapeutic targets
and to review up-to-date virus-specific clinical trials.
[Back to top]
Interactions Between Growth Hormone and the Thyroid
Gland – with Special Reference to Biochemical Diagnosis
Ulla Feldt-Rasmussen
The diagnosis of pituitary disorders is difficult because
several hormone systems are involved. The clinical presentation
is often vague and slowly progressing, and clinicians therefore
have to rely very much on correct biochemical measurements.
This is also associated with difficulties since the pituitary
hormones interact, the binding proteins are influenced by
the other axes and a variety of other effects, and finally
the hormone measurements in serum are not totally adequate
Several studies have investigated the interaction between
the thyroid and growth hormone axes with very variable results.
The present review is focussing on the aspects related to
clinical decision making based on biochemical assessments.
Because of the strong and sometimes unpredictable interrelations
between the hypothalamo-pituitary thyroid and the hypothalamo-GH-IGF
axes, and the many pitfalls in the measurement of peripheral
hormones and interpretation of stimulation tests, clinicians
and clinical biochemists should collaborate closely. Only
then can the diagnostic accuracy and the management of patients
with both growth hormone and thyroid disorders be improved.
[Back to top]
Computer Simulation of Antimicrobial Peptides
Edit Mátyus, Christian Kandt and D. Peter Tieleman
Naturally occurring and synthetic peptides may be a novel
class of clinically useful antibiotics. A large body of experimental
data on structure function relationships for such peptides
is available, but the molecular mechanism of their action
remains elusive in most cases. Computer simulations can give
detailed insights into the interactions between peptides and
lipid bilayers, at least one crucial step in the antimicrobial
mechanism. Here we review recent simulations of antimicrobial
peptides and discuss potential future contributions of computer
simulations in understanding and ultimately designing antimicrobial
peptides.
[Back to top]
Valproate and Neuroendocrine Changes in Relation to
Women Treated for Epilepsy and Bipolar Disorder: A Review
M.F. Reynolds, E.C. Sisk and N.L. Rasgon
Valproic acid (2-n-propylpentanoic acid, VPA) is well-established
as a mood-stabilizer for bipolar disorder, in addition to
its application as a treatment in neurological disorders such
as epilepsy, migraine headaches, and chronic neuropathic pain.
Its mechanisms of actions in any of the disorders have not
yet been fully elucidated but currently include GABA-ergic
inhibitory effects, the suppression of NMDA-mediated excitatory
neurotransmission, and possibly effects on monoamines and
cerebral glucose metabolism. Given the rising use of VPA by
women of reproductive age for various conditions it is increasingly
important to understand how VPA affects reproductive and metabolic
function in women, yet a number of key issues regarding VPA
use in women of reproductive age remain unclear. These include
the question of whether VPA use is associated with the development
of polycystic ovary syndrome (PCOS)-like features (such as
elevated androgen concentrations and/or chronic anovulation).
The metabolic effects of VPA use, particularly on insulin
sensitivity and weight gain, are also important to understand.
Lastly, questions of VPA use during pregnancy and lactation
require continued attention. This article reviews the current
understanding of VPA’s mechanisms of action, effects
on the reproductive and metabolic system, and teratogenic
qualities, highlighting important future areas of study.
[Back to top]
Application of the O–N Intramolecular Acyl Migration
Reaction in Medicinal Chemistry
Mariusz Skwarczynski and Yoshiaki Kiso
The O–N intramolecular acyl migration, also named as
an acyl shift or acyl transfer reaction, is well-known in
organic and peptide chemistry as a simple rearrangement which
proceeds under very mild aqueous conditions. Despite a long
history with this reaction, its application in medicinal chemistry
has only lately been proposed. In the last decade, this reaction
has been intensively studied and several applications of this
rearrangement in medicinal chemistry have appeared. O–N
Intramolecular acyl migration has been employed in “no
auxiliary, no byproduct” prodrug strategies (prodrugs
of paclitaxel and other taxoids, prodrugs of HIV protease
inhibitors), for the synthesis of peptides containing difficult
sequences via “O-acyl isopeptide method”,
including Alzheimer's disease related amyloid β
peptide (Aβ)
1–42, and in the design of pH-, photo- or enzyme-triggered
click peptides, as a potential powerful tool for identifying
the pathological functions of amyloid β
peptides in Alzheimer’s disease. This review summarized
recent advances in the application of O–N intramolecular
acyl migration with special focus on medicinal chemistry.
[Back to top]
Isoflavones, Equol and Cardiovascular Disease: Pharmacological
and Therapeutic Insights
Katherine A. Jackman, Owen L. Woodman and Christopher
G. Sobey
Isoflavones are an important class of phytoestrogens that
are found at extrememly high levels in soy. Up until recently,
daidzein and genistein were considered to be the most important
and hence most studied isoflavones, however more recently
attention has shifted to isoflavone metabolies. Equol represents
the main active product of daidzein metabolism, produced via
specific microflora in the gut. It has a longer half life
and greater biological activity, including superior antioxidant
activity. Yet, whilst the majority of animals produce equol
following soy consumption, as much as 30 – 50 % of the
adult human population cannot. This inability to produce equol
in as much as half the population is thought to provide some
explanation for the failure of soy to reveal any substantial
health benefits in clinical studies. This article will comprehensively
review literature investigating the potential cardiovascular
benefits of daidzein and its metabolites, paying particular
attention to equol. It will focus on the relative vasorelaxant
activity, effects on nitric oxide synthase (NOS), antioxidant
activity and potential for the treatment and prevention of
hypertension and stroke. Findings obtained in both animal
and human studies will be reviewed with the hope of gaining
an insight into the experimental and clinical importance of
equol to the cardiovascular benefits of soy.
[Back to top]
Synthetic Peptides: The Future of Patient
Management in Systemic Rheumatic Diseases?
Kai Kessenbrock, Reinout Raijmakers, Marvin J. Fritzler
and Michael Mahler
Since the first description of self-reactive antibodies in
systemic autoimmune rheumatic diseases, many autoantigens
have been identified as useful diagnostic biomarkers in clinical
immunology. Among the autoantigens, double-stranded desoxoribonucleic
acid (dsDNA), the Smith antigen (Sm), topoisomerase-I (topo-I),
proliferating cell nuclear antigen (PCNA), and others were
described as hallmark targets of systemic autoimmune diseases.
The detection of the corresponding autoantibodies can be performed
with a variety of immunoassays based on native antigens, recombinant
proteins or synthetic peptides. As discussed in this review,
synthetic peptides often represent highly accurate antigenic
ligands for autoantibody assays that can be easily produced
in high quality and quantity and with remarkable reproducibility.
Furthermore, the use of peptides that focus on abrogation
or neutralization of pathogenic autoantibodies provides a
possible new therapeutic approach to the management of autoimmune
disorders. There is an increasing number of interesting examples
for the application of synthetic peptides in diagnostic approaches.
Today’s sophisticated epitope mapping methods will potentate
the identification of further peptides that can be possibly
used as specific targets in diagnostic and therapeutic approaches
to improve the patients´ treatment. This may lead to
a new scientific research area with high impact on the development
of diagnostic and therapeutic products, to the area of peptide
engineering and “theranostics”.
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