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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 5, Number 10, October 2005
Contents
Pharmacological Properties of Indazole Derivatives: Recent
Developments Pp. 869
Hugo Cerecetto, Alejandra Gerpe, Mercedes González,
Vicente J. Arán and Carmen Ochoa de Ocárizi
[Abstract]
The Structure - Inhibitory Activity Relationships
Study in a Series of Cyclooxygenase 2 Inhibitors: A Combined Electronic-Topological
and Neural Networks Approach Pp. 879
A. Dimoglo, V. Kovalishyn, N. Shvets and V. Ahsen
[Abstract]
Advances in Prodrug Design Pp. 893
Antonio Távora de Albuquerque Silva, Man Chin Chung,
Lúcia Fioravanti Castro, Rafael Victorio Carvalho Güido
and Elizabeth Igne Ferreira
[Abstract]
New Anti-Alzheimer Drugs from Biodiversity: The
Role of the Natural Acetylcholinesterase Inhibitors Pp.
915
Cláudio Viegas Jr., Vanderlan da Silva Bolzani,
Eliezer J. Barreiro and Carlos Alberto Manssour Fraga
[Abstract]
Pharmacophore Identification for Sigma-1 (σ1)
Receptor Binding: Application of the “Deconstruction
– Reconstruction – Elaboration” Approach
Pp. 927
R.A. Glennon
[Abstract]
Cannabinoids and Cancer Pp. 941
Natalya M. Kogan
[Abstract]
Corticotropin-Releasing Factor Binding Protein
- A Ligand Trap? Pp. 953
Olaf Jahn, Jelena Radulovic, Oliver Stiedl, Hossein Tezval,
Klaus Eckart and Joachim Spiess
[Abstract]
Abstracts
[Back to top]
Pharmacological Properties of Indazole Derivatives: Recent
Developments
Hugo Cerecetto, Alejandra Gerpe, Mercedes González,
Vicente J. Arán and Carmen Ochoa de Ocárizi
The chemistry of indazole and its N-oxide derivatives
is very well-known. Indazole derivatives were extensively
studied as bioactive compounds, such as anti-aggregatory and
vasorelaxant activity by NO release and increase of cGMP levels
and anticancer effects, antimicrobial and antiparasitic properties,
among others. Recently, the research and development in the
medicinal chemistry of these systems have produced compounds
with contraceptive activities for men, for the treatment of
osteoporosis, inflammatory disorders and neurodegenerative
diseases. On the other hand, indazole N-oxide derivatives
were poorly studied as bioactive compounds, but recently compounds
with antiparasitic properties were produced. In this presentation,
recent developments in the chemistry and medicinal chemistry
of indazole and its N-oxide derivatives will be reviewed.
[Back to top]
The Structure - Inhibitory Activity Relationships Study in
a Series of Cyclooxygenase 2 Inhibitors: A Combined Electronic-Topological
and Neural Networks Approach
A. Dimoglo, V. Kovalishyn, N. Shvets and V. Ahsen
Structure-activity relationships study was performed for
a few series of cyclooxygenase-2 (COX-2) inhibitors by using
the Electronic-Topological Method combined with Neural Networks
(ETM-NN). Specific molecular fragments were found for active
compounds (‘activity features’) from both series
by the ETM application. After this, a system of prognosis
was developed as the result of training Kohonen’s self-organizing
maps (SOM) by the fragments. From the detailed analysis of
all compounds under study, requirements necessary for a compound
to be COX-2 inhibitor were formulated. The analysis showed
that any requirements violation for a molecule resulted in
a considerable decrease or even complete loss of its activity.
The found activity features identified correctly different
marketed drugs and new compounds that had passed pre-clinical
and clinical trials; this fact confirms the workability of
the system developed for the COX-2 inhibitory activity prediction.
[Back to top]
Advances in Prodrug Design
Antonio Távora de Albuquerque Silva, Man Chin Chung,
Lúcia Fioravanti Castro, Rafael Victorio Carvalho Güido
and Elizabeth Igne Ferreira
The background of prodrug design is presented herein as the
basis for introducing new and advanced latent systems, taking
into account mainly the versatility of polymers and other
macromolecules as carriers. PDEPT
(Polymer-Directed Enzyme
Prodrug Therapy); PELT
(Polymer-Enzyme Liposome
Therapy); CDS (Chemical
Delivery System); ADEPT(Antibody-Directed
Enzyme Prodrug Therapy);
GDEPT/VDEPT (Gene-Directed
Enzyme Prodrug Therapy/Virus-Directed
Enzyme Prodrug Therapy);
ODDS (Osteotropic
Drug Delivery System)
and LEAPT (Lectin-directed
enzyme-activated prodrug
therapy) are briefly described and some examples
are given.
[Back to top]
New Anti-Alzheimer Drugs from Biodiversity: The Role of the
Natural Acetylcholinesterase Inhibitors
Cláudio Viegas Jr., Vanderlan da Silva Bolzani,
Eliezer J. Barreiro and Carlos Alberto Manssour Fraga
Alzheimer’s disease (AD) is a progressive neurodegenerative
pathology with severe economic and social impact. There is
currently no cure, although cholinesterase inhibitors provide
effective temporary relief of symptoms in some patients. Nowadays,
drug research and development are based on the cholinergic
hypothesis that supports the cognition improvement by regulation
of the synthesis and release of acetylcholine in the brain.
There are only four commercial medicines approved for treatment
of AD, and natural products have played an important alternative
role in the research for new acetylcholinesterase inhibitors,
as exemplified through the discovery of galantamine. This
profile conducts us to give in this paper an overview relating
the several classes of natural products with anti-cholinesterasic
activity as potential templates to the design of new selective
and powerful anti-Alzheimer drugs.
[Back to top]
Pharmacophore Identification for Sigma-1 (σ1) Receptor
Binding: Application of the “Deconstruction –
Reconstruction – Elaboration” Approach
R.A. Glennon
At least two different types of sigma σ (σ1
and σ2) receptors have been identified. A
structural feature common to high-affinity (Ki <10
nM) σ1 ligands is: C-N(R)-X-Ph; both C and
Ph are associated with regions of bulk tolerance. Numerous
other ligands bind, but typically do so with lower affinity.
[Back to top]
Cannabinoids and Cancer
Natalya M. Kogan
Marijuana has been used in medicine for millennia, but it
was not until 1964 that Δ9-tetrahydrocannabinol
(Δ9-THC), its major psychoactive component,
was isolated in pure form and its structure was elucidated.
Shortly thereafter it was synthesized and became readily available.
However, it took another decade until the first report on
its antineoplastic activity appeared. In 1975, Munson discovered
that cannabinoids suppress Lewis lung carcinoma cell growth.
The mechanism of this action was shown to be inhibition of
DNA synthesis. Antiproliferative action on some other cancer
cells was also found. In spite of the promising results from
these early studies, further investigations in this area were
not reported until a few years ago, when almost simultaneously
two groups initiated research on the antiproliferative effects
of cannabinoids on cancer cells: Di Marzo's group found that
cannabinoids inhibit breast cancer cell proliferation, and
Guzman's group found that cannabinoids inhibit the growth
of C6 glioma cell. Other groups also started work in this
field, and today, a wide array of cancer cell lines that are
affected is known, and some mechanisms involved have been
elucidated.
[Back to top]
Corticotropin-Releasing Factor Binding Protein - A Ligand
Trap? Pp.953
Olaf Jahn, Jelena Radulovic, Oliver Stiedl, Hossein Tezval,
Klaus Eckart and Joachim Spiess
The actions of the neuropeptide corticotropin-releasing factor
(CRF) are modulated by a CRF binding protein (CRFBP). In view
of the memory-enhancing effects of CRF, the release of endogenous
CRF from CRFBP by CRFBP inhibitors has been suggested as a
therapeutical strategy for the treatment of cognitive deficits.
This mini-review will summarize recent advances in the field
with a focus on the pharmaceutical potential of CRFBP inhibitors.
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