Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 5, Number 12, December 2005

Contents


A_2B Adenosine Receptor Antagonists: Recent Developments Pp.1053
Barbara Cacciari, Giorgia Pastorin, Chiara Bolcato, Giampiero Spalluto,Magdalena Bacilieri and Stefano Moro
[Abstract]


Role of 1,4-Benzothiazine Derivatives in Medicinal Chemistry Pp.1061
R. Fringuelli, L. Milanese and F. Schiaffella
[Abstract]


A Re-Emerging Class of Antimicrobial Agents: Streptogramins (Quinupristin/Dalfopristin) in the Management of Multiresistant Gram-Positive Nosocomial Cocci in Hospital Setting Pp.1075
Roberto Manfredi
[Abstract]


QT Interval Prolongation: And the Beat Goes on Pp.1083
Mehran Jalaie and Daniel D. Holsworth
[Abstract]


Modulation of HIV-1 Transcription by Cytokines and Chemokines Pp.1093
K.F.T. Copeland
[Abstract]


Recent Advances in Discovery and Development of Promising Therapeutics against Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase Pp.1103
Jim Zhen Wu, Nanhua Yao, Michelle Walker and Zhi Hong
[Abstract]


Thymidine Phosphorylase Inhibitors: Recent Developments and Potential Therapeutic Applications Pp.1113
María-Jesús Pérez-Pérez, Eva-María Priego, Ana-Isabel Hernández,María-José Camarasa, Jan Balzarini and Sandra Liekens
[Abstract]


Involvement of PI3K/Akt Pathway in Prostate Cancer – Potential Strategies for Developing Targeted Therapies Pp. 1125
Nicole Pommery and Jean-Pierre Hénichart
[Abstract]


Synthetic Approaches to the 2004 New Drugs Pp.1133
Jin Li, Kevin K.-C. Liu and Subas Sakya
[Abstract]




Abstracts

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A_2B Adenosine Receptor Antagonists: Recent Developments
Barbara Cacciari, Giorgia Pastorin, Chiara Bolcato, Giampiero Spalluto,Magdalena Bacilieri and Stefano Moro

There are pharmacological evidences that A_2B receptors are involved in inflammatory processes, such as asthma. For this reason, many efforts has been made for identifying selective A_2B antagonists as anti-asthmatic agents. The updated material related to this field has been rationalised and arranged in order to offer an overview of the topic.


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Role of 1,4-Benzothiazine Derivatives in Medicinal Chemistry
R. Fringuelli, L. Milanese and F. Schiaffella

1,4-Benzothiazine (1,4-BT) derivatives have been reported to exhibit a wide range of pharmacological properties including antifungal, immunostimulating, anti-aldoso-reductase, anti-rheumatic, anti-allergic, vasorelaxant, anti-arrhythmic, anti-hypertensive, neuroprotective and cytotoxic activities. These different effects indicate that 1,4-BT is a template potentially useful in medicinal chemistry research and therapeutic applications.


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A Re-Emerging Class of Antimicrobial Agents: Streptogramins (Quinupristin/Dalfopristin) in the Management of Multiresistant Gram-Positive Nosocomial Cocci in Hospital Setting
Roberto Manfredi

Multiresistant gram-positive cocci, including Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium, are emerging pathogens in the setting of immunocompromised, hospitalized patients, especially when surgery or invasive procedures are of concern, and patients are admitted in intensive care units. The spectrum of antimicrobial compounds available for an effective treatment of these infection is significantly threatened by the emerging and spread of glycopeptide-resistant strains. Quinupristin/dalfopristin is a novel streptogramine association, which represents an effective response to most of these problems, due to its innovative mechanim of action, its maintained activity against multiresistant pathogens, and its possibility of synergistic activity with other compounds. Problems related to the epidemiology of multiresistant gram-positive infection, potential clinical indications of quinupristin/dalfopristin, and updated data on efficacy and tolerability of this compound and its derivatives, are outlined on the ground of a review of available literature evidences.


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QT Interval Prolongation: And the Beat Goes on
Mehran Jalaie and Daniel D. Holsworth

Consideration of QT interval prolongation and the risk for developing torsade de pointes is a critical issue in the evaluation of new bioactive agents. Over the past several years, there has been a dramatic increase in understanding the I_Kr channel and its role in the duration of the action potential and cardiac repolarization. Furthermore, a variety of factors and situations have been identified that can increase the risk of QT interval prolongation. In this brief summary, an overview of the hERG channel and QT prolongation will be presented. The basic electro-physiology of the heart, the related action potentials, and pre-clinical assays is reviewed. Further, an introduction to the current status of in silico efforts in predicting potential hERG blockers is discussed. Lastly, the strengths and weaknesses of each modeling method is presented along with insight to the appropriate use of each model.


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Modulation of HIV-1 Transcription by Cytokines and Chemokines
K.F.T. Copeland

Infection with HIV results in the modulation of circulating levels of many host factors. Several host proteins that are up-regulated in HIV infection have the potential to influence virus replication. More specifically, the transcription of HIV-1 can be modulated in vivo by host proteins, including cytokines and chemokines. Cytokines modulate transcription mediated by the HIV-1 long terminal repeat (LTR) via multiple signal transduction pathways with resulting recruitment of numerous transcription factors, including NFκB, C/EBP, AP-1, TCF-1α, NF-IL-6 and ISGF-3. The effects on transcription may vary depending upon the cell type studied and upon the timing of the exposure of infected or transfected cells to cytokines. Furthermore, studies of cytokine mediated activation or inhibition of LTR mediated transcription may also be affected by the presence of the HIV-1 trans-activating protein, Tat, which has significant impact upon the redox state of the cell. This review will examine the complexities of the positive and negative control of HIV transcription by cytokines and chemokines.


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Recent Advances in Discovery and Development of Promising Therapeutics against Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase
Jim Zhen Wu, Nanhua Yao, Michelle Walker and Zhi Hong

Lack of highly effective and safe therapeutics for hepatitis C virus (HCV) infection provides an opportunity as well as a challenge to discover novel and potent anti-HCV drugs. HCV NS5B RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and thus constitutes a valid target for therapeutic intervention. To date, numerous HCV NS5B RdRp inhibitors have been discovered. This review focuses on the recent advances in discovery, mechanism of action studies and biological characterization of several distinct classes of potent inhibitors for NS5B RdRp. The clinical efficacy and developmental status of several promising compounds are also outlined.


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Thymidine Phosphorylase Inhibitors: Recent Developments and Potential Therapeutic Applications
María-Jesús Pérez-Pérez, Eva-María Priego, Ana-Isabel Hernández,María-José Camarasa, Jan Balzarini and Sandra Liekens

Thymidine Phosphorylase (TPase) catalyses the reversible phosphorolysis of pyrimidine 2’-deoxynucleosides to 2-deoxyribose-1-phosphate and their respective pyrimidine bases, including the phosphorolysis of nucleoside analogues with important antiviral or anticancer properties. Moreover, TPase, identified also as the angiogenic platelet-derived endothelial cell growth factor (PD-ECGF), stimulates endothelial cell migration in vitro and angiogenesis in vivo and plays an important role in tumour progression and metastasis. Here we have summarized the most recent approaches in the search for novel TPase inhibitors together with the potential therapeutic applications of such inhibitors.


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Involvement of PI3K/Akt Pathway in Prostate Cancer – Potential Strategies for Developing Targeted Therapies
Nicole Pommery and Jean-Pierre Hénichart

This review presents some therapeutic interventions actually considered in prostate cancer therapy to compensate constitutive activation of the PI3K/Akt signalling pathway induced, particularly, by mutations of PTEN gene. Special emphasis is placed on applicability of EGF-R tyrosine kinase, COX-2, PDK-1, mTOR and farnesyltransferase inhibitors.


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Synthetic Approaches to the 2004 New Drugs
Jin Li, Kevin K.-C. Liu and Subas Sakya

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as leads for designing future drugs. To this end, this review covers the syntheses of 12 NCEs marketed in 2004.