Mini Reviews in Medicinal Chemistry - Volume 7, Issue 5, 2007

To develop the newer pharmaceuticals and to spur the strong growth, being a general property of ‘handedness’, chirality plays a major role. The Easson-Stedman principle shows the differences in the biological activity between enantiomers resulted from selective reactivity of one enantiomer with its receptor. It helps to improve the pharmacokinetic properties and to remove undesirable side effects by virtue of the unique activity of enantiomers. Racemic switching and marketing drug combinations are used as tools for drug life-cycle management and to redevelop racemic mixtures as single enantiomers.

Basic part of the current standard treatment of organophosphate (OP) agent poisoning is administration of cholinesterase reactivators. It includes different types of oximes with a similar basic structure differing by the number of pyridinium rings and by the position of the oxime group in the pyridinium ring. Oximes hydrolytically cleave the organophosphates from acetylcholinesterase (AChE), restoring enzymatic function. This reactivation of AChE is dependent on the type of the agent and, on the reactivator used. From the common oximes, mono- and bisquaternary pyridinium oximes are more or less frequently used in clinical practice such as pralidoxime, obidoxime, trimedoxime, and HI-6. Though there are data on a good therapeutic effects of reactivators, some attempts to undermine the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisonig, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. An universality of oximes able to reactivate AChE inhibited by all OP is questioned and trends (molecular modelling using neural network, structure-activity relationship, combination of reactivation and anticholinergic properties in one molecule) for future research are characterized.

Objective: To review the main pharmacological properties and clinical applications of the drugs used in the medical therapy of Cushing's syndrome. Data Sources: Search for articles were performed in the following dababases: MEDLINE, EMBASE, Cochrane Database of systematic Reviews and The Cochrane Central Register of Controlled Trials (CENTRAL). Search terms included Cushing's syndrome and drug therapy. Data Synthesis: Available data suggest that neuromodulatory compounds affect corticotropin (ACTH) or ACTH-releasing hormone (CRH) synthesis and release. They include serotonin antagonists, dopaminergic agonists, valproic acid, reserpine, somatostatin analogs and thiazolidinediones. These agents have been effective in a limited number of patients with ACTH-dependent Cushing's syndrome. Inhibitors of steroidogenesis reduce cortisol production by blocking one (metyrapone, trilostane) or several (aminoglutethimide, ketoconazole, fluconazole, etomidate) enzymes involved in steroid biosynthesis. Mitotane is a steroidogenesis inhibitor with adrenolitic properties. Mifepriston'e blocks glucocorticoid receptor activation without modifying cortisol synthesis. Conclusion: Agents that inhibit steroidogenesis are useful in all forms of Cushing's syndrome and are effective in about 70% of patients. Main indications for drug therapy include preparation for surgery, persistence or recurrence after surgery, while awaiting for the effect of radiation therapy, occult ectopic ACTH syndrome, severe hypercortisolism and malignancy related hypercortisolism.

The development of prodrugs that are enzymatically activated into anticancer agents is a promising perspective in cancer therapy. Many nitrogen-containing quinoid heterocycles have been reported to show antitumor effect. The principal interest in these compounds lies on their potential to produce tumor-selective toxicity. Selectivity occurs by difference in oxygen tension between normal and tumor tissue and by levels of the required activating enzymes. In this review a summary of the most interesting heterocyclic quinones is given together with their biological property. SAR studies concerning the importance of some structural features will be described.

The application of 2H solid-state NMR in determining structure activity relationships and mechanism of action of membrane active peptides is discussed. The enhancement of the disruption of anionic lipids in the membrane by new lead compounds is shown to be a key determinant of both DNA vector and antimicrobial activity.

In Silico predictive ADME/Tox screening of compounds is one of the hottest areas in drug discovery. To provide predictions of compound drug-like characteristics early in modern drug-discovery decision making, computational technologies have been widely accepted to develop rapid high throughput in silico ADMET analysis. It is widely perceived that the early screening of chemical entities can significantly reduce the expensive costs associated with late stage failures of drugs due to poor ADME/Tox properties. Drug toxic effects are broadly defined to include toxicity, mutagenicity, carcinogenicity, teratogenicity, neurotoxicity and immunotoxicity. Toxicity prediction techniques and structure-activity relationships relies on the accurate estimation and representation of physico-chemical and toxicological properties. This review highlights some of the freely and commercially available softwares for toxicity predictions. The information content can be utilized as a guide for the scientists involved in the drug discovery arena.

Recent evidence has suggested improved outcomes following incorporation of intraperitoneal chemotherapy administration with intravenous systemic chemotherapy as first-line treatment of small volume residual epithelial ovarian cancer. This review focuses on the mechanism of actions of the chemotherapeutic drugs and reviews the possible reasons for the superior outcomes of intraperitoneal chemotherapy.

Over the past decade, an epidemic of obesity has developed throughout the Western World. In recent years, significant interest has focused on the role of the AMP-activated protein kinase (AMPK) as a potential therapeutic target for the treatment of obesity and type 2 diabetes and is such the focus of this review. Specifically, the potential role of AMPK in skeletal muscle metabolism as it relates to the insulin sensitizing effects of exercise and the hormones, leptin, adiponectin, ciliary neurotrophic factor and interleukin-6 are discussed. We caution that despite the convincing associations between the activation of AMPK signalling and the restoration of insulin sensitivity, future studies in genetic models of AMPK deficiency or constitutive activation within skeletal muscle are needed to evaluate the quantitative role of AMPK and to validate whether strategies designed to activate skeletal muscle AMPK may be important for regulating whole-body insulin sensitivity.

An increasing body of evidence suggests that different genetic factors, such as angiotensin-converting enzyme (ACE) I/D , angiotensin II type-1 receptor (AT1R) A1166C, methylenetetrahydrofolate reductase (MTHFR) C677T and ENOS G894T variants are associated with an endothelial dysfunction (ED). EDs are relatively new phenomena that are presumed to contribute to vasoregulatory malfunctions at the small-vessel level. Ever more clinical observations indicate that the above genetic variants are also associated with cerebral small-vessel disorders. This article reviews the knowledge available on the roles of ED- associated genetic variants in cerebral circulatory disorders, and suggests that EDs can be causative factors for different common cerebral pathologies such as leukoaraiosis or/and small-vessel infarcts. Newly-developed drugs involving phosphodiesterase type-5 inhibitors, which improve the endothelial functions, may comprise a new approach to the treatment and prevention of small-vessel cerebral circulatory disorders.

Preventive doping research includes the development of methods for the detection of new or emerging drugs to be implemented in routine screening analysis. Candidates with great potential for misuse in elite sports include selective androgen receptor modulators, growth hormone secretagogues, hypoxia-inducible factor stabilizers and erythropoietin mimetics.

Asthma is a chronic respiratory condition affecting many adults and children. An association between asthma and raised gaseous nitric oxide in the exhaled breath was first reported in 1993. In the absence of an objective test for diagnosing and monitoring asthma, a vigorous research effort has subsequently sought to determine the nature of the relationship between exhaled nitric oxide (ENO) and asthma and to determine the clinical utility of ENO measurements in asthmatics. Many methodological issues relating to ENO measurements have also been addressed. The evidence indicates that ENO originates from a number of sources and the “excess” ENO in asthmatics is mostly derived from the lower respiratory epithelium where ENO probably reflects eosinophilic airway inflammation. Clinical studies have revealed that ENO may be useful in the diagnosis of atopic asthma but not non-atopic asthma. Longitudinal measurements of ENO have been found to correlate with asthma symptoms, including relapse of symptoms after cessation of corticosteroids treatment. In summary, over a relatively short time ENO has become recognised as a useful objective tool for diagnosing and monitoring asthma. More clinical studies will be required in order for ENO to become fully established in the diagnosis and management of asthma.

Natural vitamin E comprises 8 different analogues, the α-, β-, γ-, and δ-tocopherols and the α-, β-, γ-, and α-tocotrienols. However, only α-tocopherol is selectively enriched by the liver; the other vitamin E analogues and also excess α-tocopherol are converted to several metabolites and eliminated. Recently, a novel phosphorylated form of tocopherol, α-tocopheryl phosphate, was shown to occur naturally in animal and human tissues as well as in foods. Several synthetic vitamin E derivatives have been synthesized that are either converted by esterases to the natural form, or exert novel or vitamin E related biological activities. During the last years, specific cellular effects for each individual vitamin E analogue have been described that are the consequence of modulating signal transduction and gene expression. These effects possibly reflect specific interactions of each of the vitamin E analogues with enzymes, structural proteins, lipids and transcription factors. In this review, the different natural vitamin E analogues and synthetic derivatives are compiled in relation to their major molecular and cellular activities.