Anti-Obesity Drug Discovery and Development

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Obesity, a widespread and growing problem in industrialized countries, engenders many medical, psychosocial and economic issues. In 1990s, the body mass index (BMI) became a universally accepted measure of the degree of overweight and now identical cutoff points are recommended. In the Western countries, cutoff points of 25 and 30 kg/m2 are used for describing overweight and obesity. However, in Asian countries, the absolute health risk (particularly of type 2 diabetes mellitus) seems to be higher at the same level of BMI. The international obesity task force (IOTF) suggested the cutoff points to be 23 kg/m2 for overweight and 25 kg/m2 for obesity in Asian countries. Consensus for obesity treatment is that clinical therapy should begin with lifestyle changes focusing on behavioral modification, diet, and exercise. When lifestyle modification schemes are unsuccessful, drug therapy is an attractive option. The use of anti-obesity drug has become increasingly common in the last 30 years. In conclusion, the prevalence of obesity is increasing at an alarming rate in many parts of the world. Thus, increased attention should be paid to people who are at high risks. Anti-obesity drugs may be an option for weight control; however, they should be used under regulation and with caution.

The incidence of obesity is increasing dramatically worldwide. In North America alone, approximately 60% of the population is either overweight or obese. Obese individuals are at high risk for the development of metabolic disorders, including insulin resistance, type II diabetes mellitus and cardiovascular diseases (CVD). In terms of CVD, in particular, obese individuals are at increased risk for heart diseases and stroke. Dyslipidemia in obesity is a major cause of obesityrelated CVD. More specifically, the characteristic dyslipidemia of obesity is elevated plasma triglycerides and low plasma levels of high-density lipoprotein (HDL) particles. Since HDL particles carry the “good cholesterol” and are highly anti-atherogenic particles, the lowering of plasma HDL levels in obesity, is of particular concern. Moreover, with every 1% increase in plasma HDL levels, there is a 1-3% decline in CVD risk. Thus, HDL rising in obesity is an attractive therapeutic target. However, because of its complex metabolism, developing safe and potent HDL raising therapies has been a challege. In terms of nonpharmacological therapies, diet and exercise interventions only raise plasma HDL levels modestly at best (10-15%). Of the current anti-obesity therapies, orlistat and sibutramine do not raise plasma HDL levels, while rimonabant does directly increase HDL concentrations. There is concern, however, over the serious central nervous system side-effects of rimonabant. Furthermore, in terms of HDL raising pharmaceutical therapies, the most widely used are niacin and fibrates. Fibrates only achieve a modest rise (10-15%) in plasma HDL, while niacin produces a larger increase (25%); however, due to the induction of flushing with niacin, it’s use is limited. More recently, non-flushing niacin has been developed which is a promising therapy. There is currently wide interest in developing new more potent HDL raising therapies that can induce greater reductions in CVD risk than current therapies. Foremost, the initially promising cholesteryl ester transfer protein (CETP) inhibitors proved to paradoxically increase CVD risk. In contrast, infusion of HDL or its protein apolipoprotein A-I has been more effective at reducing CVD risk. Overall, there are multiple points in the HDL metabolic pathway that may be targets for future HDL drug therapies and the future in HDL drug therapy holds great promise as we understand more about HDL’s complex physiology.

Obesity is a challenging health problem in the industrialized world and in recent population studies the prevalence of overweight, obesity and abdominal obesity is constantly increasing, reaching to an epidemic proportions. The excess of body weight is associated with a low-grade systemic inflammation and a cluster of metabolic alterations such as insulin resistance, hypertension and dyslipidemia, which is presumed to play a role in the development of cardiovascular disease and type 2 diabetes mellitus. It is now well-established that adipocytes secrete proteins (adipokines) that actively control energy homeostasis, glucose and lipid metabolism, neuroendocrine and cardiovascular function and inflammatory response. Excessive levels of some adipokines such as TNF-α and IL-6 can disturb the metabolism suggesting the adipose tissue as a link between obesity, low grade inflammation and insulin resistance. In obesity, sustained weight loss has several beneficial effects on lipid metabolism, glucose tolerance and arterial blood pressure. There have been an increasing number of obese patients requiring treatment (bariatric surgery and/or diet) for weight loss. The weight loss induced by bariatric surgery causes a reduction in the inflammatory state, increasing levels of adiponectin and GLP-1, which are all related to beneficial metabolic changes described above. GLP-1 is especially related to insulinotropic properties through induced expansion of insulin secreting B-cell mass and enhanced insulin secretion. GLP-1 acts also in insulin action enhancing B-cell glucose sensitivity contributing to glycemic control after surgical procedure. So our focus in this chapter is to emphasize metabolic and inflammatory profile in obesity and its metabolic changes after weight loss.

Obesity has reached epidemic levels in the US and represents a major health and economic challenge. The weight loss process generally starts with behavioral modification and ends with surgical intervention in cases of severe or morbid obesity. Pharmacological therapies present a valid option for patients who are overweight or morbidly obese as an in addition to the role of behavioral modification, diet and exercise. This option should also be considered for post-operative patients with inadequate weight loss who are not candidates for revisional bariatric procedures. Weight loss medications (WLMs) can be divided into the following categories:

1. Noradrenergic Appetite Suppressants (NASs): more commonly used. Examples include phentermine, sibutramine, phendimetrazine, and diethylpropion.

2. Pancreatic Lipase Inhibitors (PLIs): examples include orlistat.

3. Fat Substitutes (FSs): examples include olestra which has been integrated into snack foods but not been studied as a formal weight loss medication.

4. Cannabinoid Receptor Antagonists (CRAs): examples include Rimonabant.

5. Thermogenics and Stimulators of Fat Mobilization.

There is multiple OTC and commercial brands, it is important to differentiate between the different types and their mechanism of action, for example Alli is the OTC version of orlistat with same mechanism and side effects.

Since the obesity “disease” is chronic, the medications have to be weighed carefully in terms of the risks and benefits for long term use.

Sibutramine, as a commonly used NAS, is a centrally acting serotonin/ noradrenaline reuptake inhibitor and increases thermogenesis. Studies showed weight reduction of 4.45 kg for sibutramine compared to placebo with overall improvement in the metabolic profile e.g. decreased triglycerides, increased HDL, and improved Hgb A1C. The main side effect is tachycardia; there is conflicting studies about the effect on blood pressure so overall NASs are not recommended in patients with uncontrolled hypertension, or in case of history of cardio- and cerebrovascular disease.

Orlistat, a PLI, blocks the lipolysis of dietary triglycerides. A recent meta-analysis showed mean weight loss of 2.89 kg with overall improvement of the metabolic profile especially diabetes parameters; however there was no effect on HDL and triglycerides. As mentioned, the side effects are mainly gastrointestinal but can cause considerable inconvenience for patients for example greasy diarrhea, incontinence, urgency and oily spotting. Overall it is not recommended for patients with malabsorption or cholestasis.

Rimonabant, as a CRA, inhibits the overactivation of the endocannabinoid system resulting in central anorexia. Rimonabant seems to have effects on the metabolism through the adipose tissue, liver, skeletal muscles and the pancreas. There are four published RIO trials (Rio-North America, RIO-Europe, RIO-Lipids, RIO-Diabetes), rimonabant decreased weight by 6.3-6.9 kg in the nondiabetic groups vs. placebo (-1.5-1.8 kg) (p <0.001), whereas in the diabetic subjects enrolled in RIO-Diabetes, weight loss was 5.3 vs. 1.4 kg in the placebo group with overall improvement in the metabolic profile in diabetic and non-diabetic patients. Rimonabant is contraindicated in patients with history of depression, suicidal ideation or uncontrolled psychiatric disorder.

In spite of the fact that serotonergic agents (fenfluramine, dexfenfluramine) were withdrawn from the US market in the late 1990’s secondary to their cardiovascular and pulmonary complications. At the present time, it is very important to assess the patient’s history regarding their intake as this might result in further cardiac or pulmonary evaluations.

In conclusion, WLMs have shown decrease in body weight and improved metabolic and cardiovascular risk factors. Since, the weight loss is modest, they should be considered in overweight (BMI 25 – 29.9kg/m2) or obese (BMI 30 – 34.9 kg/m2) patients and should not be considered as an alternative for surgical intervention in patients with higher BMIs. Diet, exercise and behavioral modification should always be implemented regardless of the weight loss means being applied.

Obesity is a complex disorder resulting from the interplay of genetic, environmental, behavioral factors and life style and has a significant impact on the public health. The complexity of the disorder entails multidisciplinary research efforts involving various research disciplines to enhance the understanding of the molecular mechanisms implicated in the development of the disease. The disruption of the balance between energy intake and energy expenditure which leads to obesity involves the action of many contributing factors and many molecular compounds, making high-dimensional profiling very attractive. Nonetheless, despite definite advances in omics research over the last decade, many challenges remain, including combining data from the heterogeneous sources, development of data mining tools, and integrative analysis methodologies to fully exploit various hypotheses. This review presents a brief overview of ongoing research, summarizes current methodologies, techniques, and challenges in omics approaches to obesity research, and identifies areas of further research.

The global epidemic of obesity is rapidly accelerating in both industrialized and developing countries, and has raised significant healthcare concerns worldwide. Obesity leads to numerous co-morbidities, including cardiovascular diseases (CVD), type 2 diabetes (T2D), hypertension, certain cancers, and sleep apnea. Obesity is considered an independent risk factor for CVD, and is associated with dyslipidemia, hypertension, glucose intolerance and inflammatory markers; all of which contribute to CV risk. The benefits of weight reduction to decrease cardiometabolic risk are well-documented, yet long term weight loss has been difficult to achieve. This has lead to intense efforts within the pharmaceutical industry to develop agents that result in weight loss and prevent weight regain. Numerous strategies have been directed toward decreasing food intake and/or increasing energy expenditure, yet this has met with limited success in developing a safe and effective drug. This review summarizes the underlying mechanisms contributing to CV risk in obesity, and discusses the targets that may result in novel pharmacological agents that can sustain weight loss and reduce cardio-vascular morbidity and mortality.

The concept that monoamines related to the sympathetic nervous system can act as slimming agents is very well-known. The utmost interest in this approach followed the β3- adrenergic receptor discovery and the impressive lipolytic capacities of its agonists in rodent adipocytes. However, the clinical trials using β3-adrenergic agonists have led to a very limited antiobesity clinical application. The differences between species regarding expression level and pharmacology of β3-adrenoceptors may be the cause of this missed extrapolation. In this review, the interests and limits of cultured adipocytes vs. animal models in the discovery of anti-obesity drugs are discussed. Nevertheless, biogenic amines that share β3-adrenoceptor agonist properties, are used via self-prescription to promote weight loss. The effects of one of them, octopamine is discussed in this chapter, focusing on the large species-differences that exist regarding its action on adipocytes. Even older is the wish to use of monoamine oxidase (MAO) inhibitors in the treatment of obesity. Reduction of body weight gain has been observed in rodents, but negative side-effects, such as increased aggressiveness, mouth dryness and hypertensive crises, seriously limit their antiobesity utilisation in overweight patients. More recent is the observation of the limitation of fat development by agents that inhibit amine oxidases distinct from MAO, especially the semicarbazide-sensitive amine oxidase (SSAO) highly expressed in fat cells. The impairment of adipose tissue extension induced by semicarbazide is mirroring the insulin-like actions of SSAO and MAO substrates that activate lipogenesis and inhibit lipolysis in adipocytes. Nevertheless, another mode of action cannot be eliminated. Since combined inhibition of MAO and SSAO affects adipose tissue extension, phenelzine, which inhibits MAO and SSAO, has been tested recently. In vitro, it impairs adipogenesis, and in vivo, it decreases the adiposomatic index in obese rats. Taken together, the reduction of adipose tissue development by catecholaminergic amines or by amine oxidase inhibitors warrants further studies and can prompt the search for new anti-obesity drugs.

According to the World Health Organization, obesity is a multifactorial disease with increasing frequency in many countries that can be characterized as an epidemic of major public health concern. Recognized since 1985 as a chronic disease, obesity is the second leading cause of preventable death, exceeded only by cigarette smoking. Obesity has been established as a major risk factor for diabetes, hypertension, cardiovascular disease and some cancers in both men and women. The general goals of obesity treatment are to reduce body weight, to maintain a lower body weight over the long term or to prevent further weight gain. Traditional methods to promote weight loss focus on reducing energy intake through low-calorie or low-fat diets, increasing energy expenditure by increase in physical activity, and behavioral modification. Numerous other weight loss interventions are available including pharmacotherapy, surgery to reduce food consumption and alternative therapies. Although the pharmacological treatment of obesity should not be the first therapeutic option, its use is now fully approved. Rimonabant is a selective cannabinoid-1 receptor antagonist that has been suggested to reduce hunger and consumption by affecting the endocannabinoid system. Rimonabant has entered the market in some countries as a promising new drug for obesity. However, although effective as an anti-obesity drug, rimonabant also causes serious adverse side-effects, thus is being doubted and denied for medical usage. This chapter focuses on the role of rimonabant as anti-obesity drug, elucidating the mechanisms of action, the main results of clinical trials, FDA and EMEA recommendations, and the future perspectives.

The high incidence of obesity and the lack of safe pharmaceutical agents have fuelled an increase in researches related to anti-obesity drugs. Although a number of pharmacological approaches have been investigated in recent years, few safe and therapeutically effective products have been developed. Phytochemicals are components of plants that convey healthful properties beyond their use as macronutrients or micronutrients. These compounds have biological properties such as antioxidant, modulation of detoxification enzymes, stimulation of the immune system, reduction of platelet aggregation, and modulation of hormone metabolism. Furthermore, the latest discoveries and studies on the cellular and molecular mechanisms of such phytochemicals suggest that they are potential agents in the treatment of obesity and associated diseases, and may be incorporated in food ingredients, dietary supplements, or drug components. The main focus of this chapter is to review the available information on various aspects of phytochemicals, with special reference to their effectiveness in reducing obesity and obesity-related diseases. The bioactives that have been derived from plants, including flavonoids, terpenoids, phenolic acids, and other categories of phytochemicals based on their structure, have shown interesting effects on adipose tissue such as the induction of apoptosis, the inhibition of adipocyte differentiation and lipid accumulation, and the induction of lipolysis. Besides the ample evidence of the anti-obesity effects of these phytochemicals in literature, the characterization of their properties and the accumulation of preclinical data could raise the possibility of a new application of these interesting phytochemicals as novel drug candidates or dietary supplements.

Because of the current obesity epidemic and its considerable effect on health, lifestyle, and longevity, there is a pressing need to further understand the neural pathways involved in the control of body weight, and the motivational states underlying ingestive behaviors. In a number of obese individuals, the homeostatic mechanisms that regulate energy consumption are overpowered by environmental influences, such as an abundance of highly palatable foods which are difficult to resist, and which can lead to their consumption beyond caloric need [1]. A strong liking for highly palatable foods has been linked to increased consumption [2, 3] and research has established that obese people show a greater liking and selection of sweet and fatty foods than their leaner counterparts [4-6]. Opioid peptides and opiate receptors are believed to mediate the affective response to highly palatable food [7-10]. Evidence suggests that the opioid system modulates one’s perception of the hedonic properties of food and, consequently, food consumption [10, 11]. Therefore, the endogenous opioid system is likely to play an important role in food preferences and risk for obesity. Research suggests that targeting the opioid system may be an effective treatment option for certain individuals suffering from obesity. The following chapter will review the literature on the role of the opioid system in food consumption and examine the possibility that certain drugs, which target this system, are beneficial for weight loss and the treatment of obesity.

In this chapter we review the development of melanin concentrating hormone receptor 1 (MCH-R1) antagonists as a new perspective for the pharmacological treatment of obesity. We will initially focus on melanin concentrating hormone (MCH): structure, localization and function in the regulation of feeding behavior and energy balance and two receptors for MCH in humans. We will then review the discovery of the first MCH-R1 antagonists, the drug-design strategies used to obtained new series of MCH-R1 antagonists and an analysis of their structure-activity relationship. Finally, we will evaluate the absorption, distribution, metabolism and excretion, efficacy, safety and toxicity in preclinical and clinical trials.

The discovery and the characterization of the cannabinoid receptor 1 (CBR1) as well as the finding of its involvement in the regulation of satiety, has initiated the race for the development of antagonist molecules with the admitted purpose to counteract obesity. The first one which reach the clinical trials, was the SR141716, or Rimonabant, and a large number of studies were conducted with this molecule. The RIO, STRADIVARIUS, SERENADE and ADAGIO studies clearly showed that Rimonabant led to a loss of weight, an increase of HDL-C levels, a decrease of triglycerides and blood pressure, an improvement of the insulin response and glucose uptake, as well as an increase of adiponectin levels. Surprisingly, numerous effects of this molecule seem to be linked to a peripheral action. In particular, Rimonabant has a strong anti-inflammatory action on liver and on fat cells, which could explain its beneficial effects on the insulino-resistance. However, the molecule possesses major side effects, limitating its commercial development. These effects are inherent to the central action of the CBR1 antagonists. To eliminate these problems, it will be necessary to develop molecules which have only peripheral effects. Beside this, other molecules with a more important fat specificity could be of a strong interest, such as Cholesteryl Ester Transfert Protein (CETP) inhibitors. Indeed, this type of molecules gives good clinical results with no central effect. So, despite the commercial failure of Torcetrapib, it is likely that we will see the development of several molecules targeting CETP and yet with limited side effects.

Specialized enteroendocrine cells are scattered within the gut mucosa and influenced by nutritional status. Released hormones are, besides other biological actions, involved in the regulation of food intake by mediating their information to brain centers involved in food intake regulation located in the brainstem as well as forebrain such as hypothalamic nuclei. Intestinal enteroendocrine cells produce a variety of gut peptides regulating food intake and were therefore the focus of many studies. However, recent evidence points towards a specific endocrine cell, the X/A-like cell, located within the stomach oxyntic mucosa as an important player in appetite control. Acylated ghrelin is the only known peripherally produced and centrally acting food intakestimulatory (orexigenic) peptide so far. Its major source of production is gastric X/A-like cells. Desacyl ghrelin originates from the same cell and has been recently implicated in the regulation of food intake as well. Moreover, nesfatin-1, a novel food intake-inhibitory (anorexigenic) peptide, has been identified in ghrelin-positive cells of the stomach. This suggests an important role for gastric X/A-like cells to regulate food intake. Obestatin was initially described as a ghrelin gene product with anorexigenic properties. However, consecutive studies were not able to reproduce those findings and therefore its role as food intake regulating peptide remains equivocal. Ghrelin interacts with various other intestinal peptides to regulate food intake and body weight which has to be taken into account when targeting single peptides as a potential drug treatment for obesity.

Obesity is a major global epidemic involving children and adults. According to the World Health Organization, obesity incidence will continue to rise with global estimations reaching 700 million by 2015. Thus, it is essential to investigate the nature of the obesity epidemic and potential mitigating mechanisms. In this chapter, we explore the association between obesity and inflammation and the efficacy of biochemical mimetics such a ghrelin and leptin for exercise and diet in the control of obesity-induced inflammation. We also review non-pharmaceutical obesity interventions and non-invasive means for predicting metabolic syndrome development as well as methods of obesity assessment.

The increased prevalence of obesity worldwide has led to a rise in bariatric surgeries performed each year. Bariatric surgery is currently one of the most effective interventions for weight loss. The most common procedures include gastric bypass, adjustable gastric band, jejunoileal bypass, vertical banded gastroplasty, and biliopancreatic diversion with duodenal switch. Bariatric surgery can improve various medical conditions including but not limited to diabetes, hypertension, dyslipidemia, reflux, and obstructive sleep apnea. Patients with type 2 diabetes develop increased insulin sensitivity and improvements in glucose metabolism within days after surgery. As weight loss occurs, blood pressure and cholesterol levels may improve post operatively, allowing discontinuation of medications. Due to the possible achlorhydric nature of the gastrointestinal tract, post surgery patients often do not require acid suppressing agents for reflux. Medication absorption is highly affected by post gastric bypass surgery, specifically drug solubility and surface area for absorption. These changes warrant manipulation in drug route or dose to ensure adequate delivery. As weight loss occurs, medication adjustments are essential to provide optimal bioavailability for various health related conditions. Consideration should be made for certain medications that depend on absorption site and pH of the gastrointestinal tract for solubility and proper absorption. Non-steroidal anti-inflammatory drugs, aspirin, and bisphosphonates, should be discontinued as these can cause an increased risk of stomach ulcerations if continued post surgery. Long acting and enteric coated formulations will not be absorbed as they require an extended period of time in the intestines for drug dissolution and metabolism. Patients undergoing bariatric surgery have alterations in the digestive anatomy resulting in micronutrient and mineral deficiencies requiring immediate postoperative vitamin supplementations. Nutrient deficiencies include calcium, fat soluble vitamins (A, D, E, K), thiamine, iron, folic acid, and cyanocobalamin. Calcium and vitamin D deficiencies may cause secondary hyperparathyroidism and bone softening diseases. Cyanocobalamin deficiency may lead to irreversible peripheral neuropathy. Wernicke’s encephalopathy is common in patients with thiamine deficiency. Anemia may develop in patients with iron deficiency. Due to rapid weight loss and physiological changes, patient monitoring for therapeutic effects is crucial. Recent developments in anti-obesity therapies such as bariatric surgery have revealed improvements or complete remission of multiple chronic diseases. Manipulation of the gastrointestinal tract post bariatric surgery requires medication adjustments and vitamin supplementation for optimal patient care.

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