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

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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.


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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.


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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.


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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.


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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.


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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.

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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.