Current Topics in Medicinal Chemistry - Volume 9, Issue 6, 2009

Obesity has reached epidemic proportions in industrialized countries, especially the United States, and is rapidly increasing in prevalence worldwide. Obesity is not a simply cosmetic concern, but a serious health problem. Thus, the World Health Organization (WHO) recently declared that obesity has become a global epidemic. Obesity is characterized by excess of body fat, and includes a pro-inflammatory state eventually resulting in type 2 diabetes, coronary heart disease, hypertension; furthermore it elevates the relative risk of mortality owing to cardiovascular disease. Obesity now ranks second leading cause of preventable death after smoking in the United States. Treatment of obesity involves a combination of diet, exercise and pharmacotherapy. There is growing evidence that short-term dietary changes or exercise alone cannot cure obesity as a chronic disease. Only two drugs are currently approved for chronic weight loss treatment: orlistat and sibutramine. Both have different adverse effect profiles that limit more widespread use. Clearly, new drugs are required. However, it has been difficult to successfully develop obesity drugs, because of the complexity and inadequate knowledge of pathways that modulate energy balance in the human body. This issue of Current Topics in Medicinal Chemistry focuses on the medicinal chemistry of new agents to treat obesity. First, Park at Seoul National University and Shong at Chungnam National University review the structural origin of chemical entities for anti-obesity treatment along with the rationale for drug discovery. For the clarification of the structural origin, they formed a collection of four major groups, including natural products, natural product mimetics, synthetic small molecules, and peptides/hormones. Next, Lee and coworkers at KRICT fully explore cannabinoid-1 receptor antagonists as anti-obesity agents. Recent approaches that have been employed to avoid psychiatric side effects of CB1R antagonists are summarized. The design of non-brain penetrating and peripherally acting CB1R antagonists, allosteric modulators of CB1R, and neutral antagonists for CB1R is also discussed in this review. The third review by Cheon and Jeon at KRICT describes the most recent advances in two promising targets such as melanocortin-4 (MC-4) receptor agonists and melanin concentrating hormone (MCH) receptor-1 antagonists. Although there is still a long and winding road ahead to be marketed as anti-obesity agents, the authors anticipate that two classes of agents, MC-4R agonists and MCH-R1 antagonists will be one of the most promising candidates for future anti-obesity pharmacotherapy. The next review reported by Park and coworkers at Sungkyunkwan University describes computational modeling studies conducted on ghrelin receptor (GHS-R), and melanocortin 4-receptor (MC4R), melanin concentrating hormone 1 receptor (MCH1R) and cannabinoid 1 receptor (CB1R). They also describe the uses of virtual screening methods to identify novel antagonists of MCH1R and CB1R, which provide valuable examples of the computer-aided design and structural optimization of GPCR ligands. Next, Hruby and coworkers at University of Arizona focus on melanotropins as drugs for the treatment of obesity and other feeding behaviors. They discuss current progress in these areas with special emphasis on the MC3R. MC3R is suggested as emerging target for the treatment of obesity, due to numerous recent evidences that MC3R is more strongly related to fat intake and development of metabolic syndrome than MC4R. Finally, my team at Green Cross Corp. reviewed trends in medicinal chemistry approaches toward antiobesity pharmacotherapy. The review also describes next-generation obesity pipeline drugs including Contrave, lorcaserin, and tesofensine. The review summarizes the most recent advances in selected trends in early-stage approaches to developing obesity drugs and brings some perspectives to this important disease. I express my gratitude to all the authors for their contributions to this special issue of Current Topics in Medicinal Chemistry. I hope that this issue will be an informative contribution to the field of anti-obesity and will provide a key reference for those involved in research and development for the treatment of obesity and/or metabolic disease.

In addition to its enormous impacts on an individual's quality of life, obesity is a daunting health problem in the world today and the increasing rate of obesity is now causing a severe burden on health care systems. Fortunately, the normalization or reduction of increased body fat reverses the obesity-associated morbidities, such as hypertension, glucose intolerance, dyslipidemia, and fatty liver diseases. However, the modification of lifestyle in a case of established clinical obesity is very difficult to achieve. Recent breakthroughs in relation to the molecular mechanism regulating body weight and energy metabolism give us hopes for the development of anti-obesity drugs. Even with the high social demand for an effective treatment for obesity and extensive researches, both in academia and the pharmaceutical industry, only two weight-loss drugs, sibutramine and orlistat, have been approved by the FDA for long-term treatment. In addition, the current bottleneck in drug discovery shows that a more detailed understanding of the pathogenesis of obesity is an essential element for the development of efficacious treatment. In this review article, we focus on the structural origin of chemical entities for anti-obesity treatment along with the rationale for drug discovery, rather than categorizing the clinical efficacy or pharmacological target of obesity. For the clarification of the structural origin, we formed a collection with 4 major groups, including natural products, natural product mimetics, synthetic small molecules, and peptides/hormones. This analysis might provide strategic plans for medicinal chemists, biologists, and physicians to begin an optimistic era with a new class of pharmaceutical adjuncts for obesity therapy.

Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB1R antagonists that serve as anti obesity drugs. As a result, a number of compounds reached various stages of clinical trials by late 2008. However, the announcement by Sanofi-Aventis that they were discontinuing all ongoing trials with rimonabant, as a result of the finding that risks associated with depression and anxiety outweighed its benefits, had a major impact on this area. A wave of terminations of programs targeting the development of CB1R blockers for treatment of obesity ensued. However, abandoning this CB1R therapeutic target for anti-obesity drug development seems to be premature, since there are a number of potential approaches have been uncovered to circumvent the problems of the current agents. In this review, we summarize advances that have been made and the status of studies of a diverse array of CB1R antagonists that have been identified mainly based on modifications of the first-in-class CB1R antagonist, rimonabant. Various approaches have been employed to design these analogs, such as bioisosteric replacement, introduction of conformational constraints, scaffold hopping and ligand-based molecular modeling. In addition, current approaches that have been uncovered to avoid psychiatric side effects of CB1R antagonists are summarized. Finally, the design of non-brain penetrating and peripherally acting CB1R antagonists, allosteric modulators of CB1R, and neutral antagonists for CB1R is also discussed in this review.

Despite remarkable progress in the elucidation of energy balance and regulation, the development of new antiobesity drugs is still at the stage of infancy. Herein we briefly reviewed several investigational anti-obesity agents currently under development, consisting of agents controlling appetite, modulating nutrient absorption and lipid metabolism, sensing and regulating nutrient status, stimulating energy expenditure, and reducing adiposity. In particular, two promising targets such as melanocortin-4 (MC-4) receptor and melanin concentrating hormone (MCH)-1 receptor will be highlighted in this review covering major medicinal chemistry efforts and biological aspects of the compounds synthesized. Considering the enthusiastic efforts to develop efficacious and safe anti-obesity drugs, a range of novel medications treating obesity more effectively than is currently managed by pharmacotherapy will be available in near future.

Many orphan G-protein-coupled receptors (GPCR) have emerged as potential obesity targets. The authors are interested in the computer-aided discovery and development of small molecule anti-obesity agents targeting GPCR. Computational modeling studies have mainly been conducted on ghrelin receptor (GHS-R), melanocortin 4-receptor (MC4R), melanin-concentrating hormone 1 receptor (MCH1R) and cannabinoid 1 receptor (CB1R) in recent publications. Here, a homology modeling strategy for these receptors will be introduced, and the key structural features of their active and inactive conformations will be reviewed. In addition, the authors describe the uses of virtual screening methods to identify novel antagonists of MCH1R and CB1R, which provide valuable examples of the computer-aided design and structural optimization of GPCR ligands.

Current biological and pharmacological evidence suggests that the melanocortin 4 and melanocortin 3 receptors which are seven transmembrane G-protein coupled receptors (GPCRs) are involved in various aspects of energy balance and feeding behaviors in animals including humans. The natural endogenous ligands for these receptors are products of the gene pro-opiomelanocortin (POMC), and include α-melanocyte stimulating hormone, γ-melanocyte stimulating hormone and perhaps other modified products of POMC. Thus well designed agonists and antagonists of these ligands might serve as drugs for the treatment of feeding disorders. However, these melanotropin peptides also can have other biological activities that involve the MC3R and MC4R, and these other biological properties will need to be modulated in ligands that are likely to be useful drugs for feeding disorders. Current progress in these areas with special emphasis on the MC3R will be discussed along with possible new directions that might be fruitful in these important aspects of contemporary biology and medicine.

The prevalences of overweightedness and obesity are increasing globally at frightening rates, driven by social and economic changes. Furthermore, obesity is associated with the pathogeneses of major diseases, particularly diabetes and cardiovascular diseases. However, no satisfactorily safe, effective obesity drugs are commercially available at the present time. Only two drugs have been approved in the United States for the long-term treatment of obesity, sibutramine and orlistat. However, these drugs are minimally effective and have significant side effects, which are likely inhibit their use. Therefore, there is a huge opportunity to make a significant impact on the lives of obese people through the discovery and development of additional pharmacotherapeutic options. In this review article, the authors focus on selected trends in medicinal chemistry and the approaches used to develop drugs for treating obesity.