Editorial [Hot Topic: The Medicinal Chemistry of New Agents to Treat Obesity (Guest Editor: Jinhwa Lee)]

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.