Pharmacotherapy of obesity: emerging drugs and targets

Background: Obesity and its associated morbidities are the effects of imbalance between energy intake and expenditure. Present drugs either regulate food intake by acting on neural circuits or reduce nutrient absorption from gut. These approaches have shown moderate success, with several safety concerns, leaving an unmet need for effective and safe therapy for obesity. Objective: To provide a brief background on obesity, summarize approved drugs and give an overview of emerging therapeutic targets, their potential benefits and disadvantages. Methods: A review based on information available from medical literature. Conclusions: Potential anti-obesity targets investigated can be classified into five broad categories: i) decreasing appetite through central action; ii) increasing metabolic rate or affecting metabolism through peripheral action; iii) modulating gut peptide receptors; iv) modulating targets to affect overall cardiometabolic parameters; and v) combination therapies directed against several targets.     

Adipose targets for obesity drug development

The prevalence of obesity is increasing rapidly in most parts of the world and effective therapeutic drugs are urgently needed. The discovery of leptin in 1994 initiated a new understanding of adipose tissue function, and adipose tissue is now known to not only store and release fatty acids, but also to produce a wealth of factors that have an impact on the regulation of body weight and blood glucose homeostasis. Also, adipocytes express proteins that engage signalling pathways playing important roles in fuel substrate and energy metabolism. These proteins constitute a diverse array of adipose target candidates for the development of drugs to treat obesity. Some of these potential targets have been validated and are now in drug development stages, providing hope that the current obesity epidemic can be addressed by effective drug treatments in the near future.     

Innovative cancer drug targets: genomics,transcriptomics and clinomics

In men, gonadal function is affected in a slow, progressive way as part of the normal ageing process. Recently, however, significant interest has developed on the importance of this condition, which is variously known as male climacteric, andropause or, more appropriately, androgen decline in the ageing male (ADAM). The term andropause is biologically wrong and clinically inappropriate but, it adequately conveys the concept of emotional and physical changes that, although related to ageing in general, are also associated with significant hormonal alterations. The inappropriateness of the term is based on the fact that in women, the reproductive cycle invariably ends with ovarian failure. In men, this process is not universal and when it occurs it is normally subtle in its clinical manifestations. This has led to a tendency to ignore the syndrome as an unavoidable and untreatable result of the ageing process. For the sake of simplicity and directness, this review will use the terms ADAM and andropause to denote the global hormonal alterations associated with ageing.     

Peripheral neural targets in obesity

Interest in pharmacological treatments for obesity that act in the brain to reduce appetite has increased exponentially over recent years, but failures of clinical trials and withdrawals due to adverse effects have so far precluded any success. Treatments that do not act within the brain are, in contrast, a neglected area of research and development. This is despite the fact that a vast wealth of molecular mechanisms exists within the gut epithelium and vagal afferent system that could be manipulated to increase satiety. Here we discuss mechano- and chemosensory pathways from the gut involved in appetite suppression, and distinguish between gastric and intestinal vagal afferent pathways in terms of their basic physiology and activation by enteroendocrine factors. Gastric bypass surgery makes use of this system by exposing areas of the intestine to greater nutrient loads resulting in greater satiety hormone release and reduced food intake. A non-surgical approach to this system is preferable for many reasons. This review details where the opportunities may lie for such approaches by describing nutrient-sensing mechanisms throughout the gastrointestinal tract.     

Hypothalamic peptides as drug targets for obesity

The importance of the melanocortin system in obesity has been confirmed by the recent discovery of mutations in the melanocortin MC4 receptor in morbidly obese patients and the finding that intranasal administration of a fragment of melanocortin decreases body fat in humans. Transgenic mice overexpressing melanin-concentrating hormone (MCH) are obese and a second MCH receptor has been identified. In addition, ghrelin, endocannabinoids and glucagon-like peptide 2 have been identified as potentially important central regulators of food intake.     

Chemical genomics and emerging DNA technologies in the identification of drug mechanisms and drug targets

Chemical genomics combines chemistry with molecular biology as a means of exploring the function of unknown proteins or identifying the proteins responsible for a particular phenotype induced by a small cell-permeable bioactive molecule. Chemical genomics therefore has the potential to identify and validate therapeutic targets and to discover drug candidates for rapidly and effectively generating new interventions for human diseases. The recent emergence of genomic technologies and their application on genetically tractable model organisms like Drosophila melanogaster, Caenorhabditis elegans and Saccharomyces cerevisiae have provided momentum to cell biological and biomedical research, particularly in the functional characterization of gene functions and the identification of novel drug targets. We therefore anticipate that chemical genomics and the vast development of genomic technologies will play critical roles in the genomic age of biological research and drug discovery. In the present review we discuss how simple biological model organisms can be used as screening platforms in combination with emerging genomic technologies to advance the identification of potential drugs and their molecular mechanisms of action.     

Metabolic control of female puberty: potential therapeutic targets

Introduction: The onset of puberty in females is highly sensitive to the nutritional status and the amount of energy reserves of the organism. This metabolic information is sensed and transmitted to hypothalamic GnRH neurons, considered to be ultimately responsible for triggering puberty through the coordinated action of different peripheral hormones, central neurotransmitters, and molecular mediators.

Areas covered: This article will review and discuss (i) the relevant actions of the adipose hormone leptin, as a stimulatory/permissive signal, and the gut hormone ghrelin, as an inhibitory factor, in the metabolic control of female puberty; (ii) the crucial role of the hypothalamic kisspeptin neurons, recently emerged as essential gatekeepers of puberty, in transmitting this metabolic information to GnRH neurons; and (iii) the potential involvement of key cellular energy sensors, such as mTOR, as molecular mediators in this setting.

Expert opinion: The thorough characterization of the physiological roles of the above elements in the metabolic control of female puberty, along with the discovery of novel factors, pathways, and mechanisms involved, will promote our understanding of the complex networks connecting metabolism and puberty and, ultimately, will aid in the design of target-specific treatments for female pubertal disorders linked to conditions of metabolic stress.     

Functional genomics approaches for the identification and validation of antifungal drug targets

So far, antifungal drug discovery seems to have benefited little from the enormous advances in the field of genomics in the last decade. Although it has become clear that traditional drug screening is not delivering the long-awaited novel potent antifungals, little has been reported on efforts to use novel genome-based methodologies in the quest for new drugs acting on human pathogenic fungi. Although the market for a novel systemic and even topical broad-spectrum antifungal appears considerable, many large pharmaceutical companies have decided to scale back their activities in antifungal drug discovery. Here we report on some of the recent advances in genomics-based technologies that will allow us not only to identify and validate novel drug targets but hopefully also to discover active therapeutic agents. Novel drug targets have already been found by 'en masse' gene inactivation strategies (e.g. using antisense RNA inhibition). In addition, genome expression profiling using DNA microarrays helps to assign gene function but also to understand better the mechanism of action of known drugs (e.g. itraconazole) and to elucidate how new drug candidates work. No doubt, we have a long way to go just to catch up with the advances made in other therapeutic areas, but all tools are at hand to derive practical benefits from the genomics revolution. The next few years should prove a very exciting time in the history of antifungal drug discovery.     

Protein tyrosine phosphatases as drug targets: PTP1B and beyond

Protein tyrosine phosphatases (PTPs) control signal transduction pathways and have recently emerged as potential drug targets. Inhibition of individual PTPs can result in the activation of therapeutically relevant kinase cascades. This is particularly useful in cases where disease is associated with hormonal resistance, such as insensitivity to insulin or leptin. Currently, PTP1B is being investigated by a number of companies as a promising target for leptin/insulin mimetics and in the treatment of diabetes and obesity. Since all 90 – 100 PTPs have been identified in the human genome, the challenge now is to identify the function of these enzymes and the therapeutic indications that may exist for specific PTP inhibitors.     

Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity

Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. Rimonabant is also being tested as a potential anti-smoking treatment since endocannabinoids are related to the pleasurable effect of nicotine. Thus, rimonabant constitutes a new therapeutic approach to obesity and cardiovascular risk factors. Studies show effectiveness in weight loss; however, side effects such as psychiatric alterations have been reported, including depression and anxiety. These side effects have led the FDA(Food and Drug Administration) to not approve this drug in the United States. For a more complete evaluation on the safety of this drug, additional studies are in progress.     

Structural genomics: bridging functional genomics and structure-based drug design

Considerable advances in structural genomics have been witnessed in the last year. Several pilot studies have begun to report their initial results, and new centers have been funded to join the endeavor. The legacies of the genome sequencing efforts, namely high-throughput molecular biology and whole-organism genome sequences, have been integrated as front-end modules for structural genomics pipelines. Impressive advances have been made in NMR spectroscopy and X-ray crystallography. New methods in structural bioinformatics and computational chemistry have been published that provide the means to exploit the wealth of new information in drug discovery. Not surprisingly, the biopharmaceutical industry has been quick to recognize the benefits of these new developments and has begun to adopt them. This article reviews recent results from structural genomics initiatives and the potential applications of new information and technologies in the drug discovery process.     

Blood-brain barrier genomics and proteomics: elucidating phenotype, identifying disease targets and enabling brain drug delivery

The blood-brain barrier (BBB) regulates the passage of material between the bloodstream and the brain. Recent genomic and proteomic studies of the BBB have identified some of the unique molecular characteristics of this vascular bed, and have reinforced the concept that the BBB is heavily involved in brain function. Genomic and proteomic techniques have also been used to analyze the molecular events underlying diseases that have BBB involvement, such as multiple sclerosis, Alzheimer's disease, stroke and HIV-1 infection. It is expected that a better understanding of the complex mechanisms that link the BBB to neurological disease will ultimately lead to the development of innovative treatments.     

Deductive genomics: a functional approach to identify innovative drug targets in the post-genome era

The sequencing of the human genome has generated a drug discovery process that is based on sequence analysis and hypothesis-driven (inductive) prediction of gene function. This approach, which we term inductive genomics, is currently dominating the efforts of the pharmaceutical industry to identify new drug targets. According to recent studies, this sequence-driven discovery process is paradoxically increasing the average cost of drug development, thus falling short of the promise of the Human Genome Project to simplify the creation of much needed novel therapeutics. In the early stages of discovery, the flurry of new gene sequences makes it difficult to pick and prioritize the most promising product candidates for product development, as with existing technologies important decisions have to be based on circumstantial evidence that does not strongly predict therapeutic potential. This is because the physiological function of a potential target cannot be predicted by gene sequence analysis and in vitro technologies alone. In contrast, deductive genomics, or large-scale forward genetics, bridges the gap between sequence and function by providing a function-driven in vivo screen of a highly orthologous mammalian model genome for medically relevant physiological functions and drug targets. This approach allows drug discovery to move beyond the focus on sequence-driven identification of new members of classical drug-able protein families towards the biology-driven identification of innovative targets and biological pathways.     

New central targets for the treatment of obesity

The review focuses on the central neuronal circuits involved in energy homeostasis and the opportunities these offer for pharmacological intervention to decrease feeding behaviour and reduce weight. This article is based on the presentation ‘New central targets for the treatment of obesity’ (Sargent, British Pharmacological society, Clinical Section Symposium, December 2008).Central neuronal substrates controlling weight offer numerous opportunities for pharmacological intervention. These opportunities range from non-specific enhancement of monoamine signalling (triple reuptake inhibitors) to targeting specific monoamine receptor subtypes (5-HT_2c and 5-HT₆). The data reviewed suggest that these approaches will lead to weight loss; whether this is sufficient to produce clinically meaningful effect remains to be determined. Combination therapy targeting more than one mechanism may be a means of increasing the magnitude of the response. Preclinical studies also suggest that novel approaches targeting specific neuronal pathways within the hypothalamus, e.g. MCH₁ receptor antagonism, offer an opportunity for weight reduction. However, these approaches are at an early stage and clinical studies will be needed to determine if these novel approaches lead to clinically meaningful weight loss and improvements in co-morbid conditions such as diabetes and cardiovascular disorders.