|
Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 5, May 2006
Contents
ACE Inhibitor-Angiotensin Receptor Blocker Combinations: A
Clinician’s Perspective Pp. 491-497
T.W.R. Doulton
[Abstract]
Topical Imiquimod: Mechanism of Action
and Clinical Applications Pp. 499-503
David Vidal
[Abstract]
Antioxidative Actions of Statins: Potential Mechanisms for
Antiathersclerotic Effects Pp. 505-508
Takanori Watanabe, Kenichi Yasunari and Munehoro Nakamura
[Abstract]
Regulatory T Cells in Cancer Biology:
A Possible New Target for Biochemical Therapies Pp.
509-513
Dominik Wolf, Holger Rumpold and Anna-Maria Wolf
[Abstract]
Rational Design of Non-Hydroxamate
Histone Deacetylase Inhibitors Pp. 515-526
Takayoshi Suzuki and Naoki Miyata
[Abstract]
Small Molecule and Biologic Modulators
of the Immune Response to Hepatitis C Virus Pp. 527-531
M.L. Mbow, A. Eaton-Bassiri, W.G. Glass, A.M. Del Vecchio
and R.T. Sarisky
[Abstract]
Ether Lipids as Anticancer Agents:
Focus on Non-Phosphorus Cationic Glycerolipids Pp.
533-542
N.V. Plyavnik, A.A. Shtil and G.A. Serebrennikova
[Abstract]
Reconsideration of Japanese Traditional
Herbal Medicine: New Field of Research and Clinical Medicine
Pp. 543-547
Hideki Okamoto
[Abstract]
Molecular Insights into the Mechanisms of HIV-1 Reverse
Transcriptase Resistance to Nucleoside Analogs Pp.
549-555
Alexandra P. Carvalho, Pedro A. Fernandes and Maria J.
Ramos
[Abstract]
Novel Anti-Viral Therapy: Drugs that Block HIV
Entry at Different Target Sites Pp. 557-562
Sandra Siegert, Peter Schnierle and Barbara S. Schnierle
[Abstract]
Fine Tuning of PPAR Ligands for Type 2 Diabetes and Metabolic
Syndrome Pp. 563-573
Uma Ramachandran, Rakesh Kumar and Amit Mittal
[Abstract]
Pharmacological and Clinical Studies on Purine Nucleoside
Analogs- New Anticancer Agents Pp. 575-581
E. Lech-Maranda, A. Korycka and T. Robak
[Abstract]
The Emergence of Plasma Membrane Calcium Pump as a Novel Therapeutic
Target for Heart Disease Pp. 583-588
Delvac Oceandy, Mamta H. Buch, Elizabeth J. Cartwright
and Ludwig Neyses
[Abstract]
Recent Advances in Clarifying Prion Protein Functions Using
Knockout Mice and Derived Cell Lines Pp. 589-601
Akikazu Sakudo, Takashi Onodera, Yoshikazu Suganuma,
Takanori Kobayashi, Keiichi Saeki and Kazuyoshi Ikuta
[Abstract]
The Therapeutic Potential of Angiotensin-(1-7)
as a Novel Renin-Angiotensin System Mediator Pp.
603-609
Ana Cristina Simões e Silva, Sérgio Veloso
Brant Pinheiro, Regina Maria Pereira,Anderson José
Ferreira and Robson Augusto Souza Santos
[Abstract]
Abstracts
[Back to top]
ACE Inhibitor-Angiotensin Receptor Blocker Combinations:
A Clinician’s Perspective
T.W.R. Doulton
ACE Inhibitors (ACEI) and angiotensin receptor blockers (ARB)
inhibit the renin-angiotensin system, but ACEI may do so incompletely
when administered as monotherapy at conventional doses. In
theory, combining an ACEI and ARB might be beneficial, whereas
clinical evidence for this approach in hypertension is lacking.
An ACEI-ARB combination is likely to be useful in proteinuric
renal disease, but recent experimental evidence suggests that
very high dose monotherapy with an ARB may be the best approach.
However, the results of large outcome studies for combinations
vs. ACEI or ARB monotherapy are still awaited.
[Back to top]
Topical Imiquimod: Mechanism of Action and
Clinical Applications
David Vidal
Imiquimod is a synthetic imidazoquinoline heterocyclic amine
of 240.3 Da (C14H16N4). Imiquimod is a cytokine inducer and
a modifier of the innate immune response, as well as acquired
antiviral and antitumor immune responses. Imiquimod 5% cream
has proven to be an effective treatment for external genital
warts, superficial basal cell carcinoma, and actinic keratosis.
[Back to top]
Antioxidative Actions of Statins: Potential
Mechanisms for Antiathersclerotic Effects
Takanori Watanabe, Kenichi Yasunari and Munehoro Nakamura
Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase
(statins) are widely used for the prevention of atherosclerotic
diseases. The effects of statins on the generation of reactive
oxygen species (ROS) by in vitro and in vivo
were studied. Administration of statins significantly decreased
ROS generation in vitro and in vivo.
[Back to top]
Regulatory T Cells in Cancer Biology: A Possible
New Target for Biochemical Therapies
Dominik Wolf, Holger Rumpold and Anna-Maria Wolf
CD4+CD25+ T cells are essential for
maintenance of self-tolerance and therefore have been referred
to as regulatory T cells (Treg). Experimental tumor models
revealed that Treg are potent inhibitors of an anti-tumor
immune response. Treg are expanded in human cancer. Currently,
a variety of strategies for the induction of a specific anti-tumor
immune response are tested in preclinical and clinical settings.
Biochemical strategies modifying and/or depleting Treg in
cancer patients for an enhancement of vaccine-based therapeutic
concepts will be discussed in detail in this review.
[Back to top]
Rational Design of Non-Hydroxamate Histone
Deacetylase Inhibitors
Takayoshi Suzuki and Naoki Miyata
While most inhibitors of histone deacetylases (HDACs) are
hydroxamic acid derivatives, several non-hydroxamates have
recently been developed as inhibitors and attracted quite
a deal of attention. In this review, we present the rational
design, inhibitory effect and antiproliferative activity of
non-hydroxamate HDAC inhibitors.
[Back to top]
Small Molecule and Biologic Modulators of
the Immune Response to Hepatitis C Virus
M.L. Mbow, A. Eaton-Bassiri, W.G. Glass, A.M. Del Vecchio
and R.T. Sarisky
Hepatitis C virus represents a major global health problem,
with approximately 3% of the world population infected. Immune-response
modifiers represent the standard of care, given the lack of
approved antiviral agents having direct activity against the
viral proteins. Although in recent years, improvements in
therapy have been attained by combined treatment with pegylated
interferon and ribavirin, the discovery and development of
next-generation small molecule and biologic agents is ongoing.
Several of these newer therapeutics are focused on modulating
Toll-like receptors, interferon-alpha signaling, and the pro-inflammatory
cytokine balance. A comprehensive account of the lead compounds
in development, the bioassays used for optimization of these
immune response modifiers and their clinical status is presented.
[Back to top]
Ether Lipids as Anticancer Agents: Focus
on Non-Phosphorus Cationic Glycerolipids
N.V. Plyavnik, A.A. Shtil and G.A. Serebrennikova
This review focuses on the synthesis and mechanisms of antitumor
activity of cationic non-phosphorus analogs of edelfosine.
The role of variable length and mode of conjugation of the
spacer group, the types of cationic ‘head’, and
the length of the substituent at C(2) atom of the glycerol
backbone are discussed, providing the basis for rational design
of lipophilic anticancer drugs, in particular, for elimination
of multidrug resistant cells.
[Back to top]
Reconsideration of Japanese Traditional Herbal
Medicine: New Field of Research and Clinical Medicine
Hideki Okamoto
Japanese traditional herbal medicine, which is known as “Kampo”,
has received increasing attention as an alternative approach
to the treatment of various diseases. In order to safely and
effectively apply Kampo, it is essential to understand
oriental diagnostics. Herein, an outline of such diagnostics
is introduced, and current trends in Kampo research
are reviewed.
[Back to top]
Molecular Insights into the Mechanisms of
HIV-1 Reverse Transcriptase Resistance to Nucleoside Analogs
Alexandra P. Carvalho, Pedro A. Fernandes and Maria J.
Ramos
The causative agent of acquired immunodeficiency syndrome,
HIV-1, depends on one of its enzymes, reverse transcriptase,
to copy its single stranded RNA genome into a double stranded
DNA nucleic acid suitable for integration in the host cell
genome. In the last two decades, the advances in the knowledge
of the kinetic mechanism of reverse transcription and in the
determination of the crystallographic structures for the complexes
of the enzyme with substrates and products were huge. However,
all of this knowledge resulted in the design of RT inhibitors
for which the virus, after a short period of exposure, becomes
less susceptible, due to the development of resistance. The
development of resistance is caused by the high frequency
of viral mutation and the toxicity of those same drugs. Therefore,
a closer look at all the available information might shed
some light into this subject and help to develop new strategies
to overcome the lack of long term clinical efficiency of these
drugs. Here, we present a critical atomic level study of all
the mutations that have been detected and reported so far,
as a reaction of the enzyme to counteract the action of the
inhibitors.
[Back to top]
Novel Anti-Viral Therapy: Drugs that Block HIV Entry
at Different Target Sites
Sandra Siegert, Peter Schnierle and Barbara S. Schnierle
Drugs that block the entry of human immunodeficiency virus
type 1 (HIV-1) into host cells abrogate the establishment
of a productive infection and should ideally diminish the
chances of HIV-1 developing resistance. This review will give
an overview of the mechanism by which the envelope glycoprotein
mediates HIV-1 entry and will summarize current drug developments.
[Back to top]
Fine Tuning of PPAR Ligands for Type 2 Diabetes and Metabolic
Syndrome
Uma Ramachandran, Rakesh Kumar and Amit Mittal
Type 2 diabetes mellitus (T2DM) is highly prevalent chronic
disease. Recently, many biological targets are discovered
for treatment of this disease. The identification of the nuclear
hormone receptor peroxisome proliferator activated receptors
(PPAR) and their subtypes α,
γ and
δ or
β as
targets for controlling lipid, glucose and energy homeostasis
has proved to be exciting. As hyperlipidaemia, obesity and
insulin resistance are independent risk factors for coronary
heart disease and macrovascular complications of diabetes;
new agents that increase insulin sensitivity as well as decrease
hyperlipidaemia by distinct yet complementary mechanism are
being studied as they may provide improved therapy for T2DM
and related disorders. In this article, we review highly potent
PPARγ
agonists, PPARα/γ
dual agonists, PPAR pan agonists, alternative PPAR ligands
like partial agonists or selective PPAR modulators (SPPARMs)
and antagonists from a chemist point of view.
[Back to top]
Pharmacological and Clinical Studies on Purine Nucleoside
Analogs- New Anticancer Agents
E. Lech-Maranda, A. Korycka and T. Robak
More recently, three novel purine nucleoside analogs, including
clofarabine, nelarabine and immucillin H, have been introduced
into clinical trials. These agents have different metabolic
properties, novel mechanism of action, and are undergoing
phase I-II clinical studies for the treatment of hematopoietic
malignancies. Pharmacology and anticancer activity of PNA
are the subjects of this review.
[Back to top]
The Emergence of Plasma Membrane Calcium Pump as a
Novel Therapeutic Target for Heart Disease
Delvac Oceandy, Mamta H. Buch, Elizabeth J. Cartwright
and Ludwig Neyses
The plasma membrane calcium/calmodulin dependent ATPase (PMCA)
is a calcium-extruding enzymatic pump important in the control
of intracellular calcium concentration. PMCA is the only system
for calcium extrusion in the majority of cells. In excitable
cells such as cardiomyocytes however, PMCA has been shown
to play only a minor role in calcium homeostasis. In these
cells the main mechanism of calcium extrusion is the sodium
calcium exchanger. However, increasing evidence points to
an important role for PMCA in signal transduction; in particular
in the nitric oxide signalling pathway. In this review we
will discuss recent advances that support a key role for PMCA
in signal transduction and the potential for therapeutic targeting
of this molecule in the treatment of cardiac diseases.
[Back to top]
Recent Advances in Clarifying Prion Protein Functions Using
Knockout Mice and Derived Cell Lines
Akikazu Sakudo, Takashi Onodera, Yoshikazu Suganuma,
Takanori Kobayashi, Keiichi Saeki and Kazuyoshi Ikuta
Considerable information on the functions of prion protein
(PrP) has been accumulated. One experimental approach is the
use of PrP gene-knockout mice and derived cell lines. This
approach has contributed to elucidating the functions of cellular
prion protein (PrPC), such as its anti-oxidative
and anti-apoptotic roles. This review will introduce the recent
advances in prion biology made possible by the availability
of these tools.
[Back to top]
The Therapeutic Potential of Angiotensin-(1-7) as
a Novel Renin-Angiotensin System Mediator
Ana Cristina Simões e Silva, Sérgio Veloso
Brant Pinheiro, Regina Maria Pereira,Anderson José
Ferreira and Robson Augusto Souza Santos
In this review, we show Angiotensin-(1-7) as a novel Renin
Angiotensin System mediator that antagonizes cardiovascular
and proliferative effects of Angiotensin II and exerts complex
renal actions. We also speculate the possibility of new drugs
for the treatment of cardiovascular, genitourinary and hepatic
diseases by interfering with ACE2-Angiotensin-(1-7)-Mas axis.
|
