Editorial [Hot Topic: Opportunities and Potential Challenges for the Treatment of Metabolic Syndrome (Guest Editors: Kak-Shan Shia and Yu-Sheng Chao)]

The term “metabolic syndrome” refers to a group of abnormalities, including glucose intolerance, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hypertension, which collectively constitute the risk factors for cardiovascular disease. Originally coined in the late 1950s, metabolic syndrome has received much attention in recent years as the cardiovascular complications resulted from metabolic disorders has become a global health threat. Numerous studies have implicated obesity and insulin resistance as the two major etiological factors for metabolic disorders. Consequently, many pharmaceutical research and development efforts have been focused on developing agents to induce weight loss and improve glucose regulation. Although current therapeutic options for treating obesity and related metabolic disorders remain limited and ineffective, recent advances have identified a group of novel targets and discovered potential therapeutic agents which may offer long-term anti-obesity and antihyperglycemic effect with better safety profiles. This special issue describes molecular mechanisms underlying five emerging targets and the rationale that leads to the development of these promising molecules, which may become the next classes of anti-diabetic agents in the future. An effective strategy for weight control is to curb the food craving by blocking neuroendocrine system that stimulates food consumption. The cannabinoid-1 (CB1) receptor has been shown to play a role in the regulation of appetitive behavior and represent an attractive target for anti-obesity agent. Indeed, impressive therapeutic efficacy of CB1 antagonists has been demonstrated in animals and humans. However, the first approved CB1 antagonist, Rimonabant, was withdrawn from the market due to severe CNS side effects. Ever since, research interest in CB1 antagonist has focused on peripherally restricted CB1 antagonists in hope to preserve the sustained anti-obesity effect without any detrimental CNS side effects. The first review by Wu et al describes recent advances in the development of peripherally acting CB1 antagonists. The article focuses on how various synthetic approaches, including increasing polarity, water solubility and polar surface area, were used to restrict tissue distribution of these newly discovered agents. The authors also summarize the preclinical efficacy results on some of the promising agents. Besides CB1 receptor, pharmaceutical researchers also actively explore other neuroendocrine system for new alternatives to manage the metabolic disorders associated with obesity. In the second review, Plancher discusses recent advances in the biology and pharmacology of histamine H3 receptor, an emerging molecular target for cognitive and metabolic disorder. The review describes critical pharmacological experiments linking the H3 receptor agents and metabolic disease models as well as pharmacophore and homology models used in the design of H3 receptor agents. The article also summarizes the major hurdles and some of the contradictions seen in the H3R field, together with a brief overview of the ongoing clinical trials. Following the two anti-obesity agents, three potential anti-diabetic agents aiming at restoring metabolic homeostasis are discussed. The review from Chen and Jiaang focuses on current advances and therapeutic potential of agents targeting dipeptidyl peptidases-4 (DPP4). DPP4 is a serine protease involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 regulates glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and delaying gastric emptying. Inhibitors of DPP4 prevent the degradation of GLP-1 and have been shown to provide therapeutic benefits for type 2 diabetes. The review summarizes important structural classes of DPP4 inhibitors, emphasizing mainly on their potency and selectivity over other related peptidases. Biological activity, selective inhibitors, and therapeutic potential for related peptidases are also discussed. The next review by Sun, Wang and Wang describes small molecule inhibitors for 11-beta hydroxysteroid dehydrogenase type 1 (11β- HSD1), an NADPH-dependent enzyme catalyzing the interconversion of inactive cortisone to active cortisol. 11β-HSD1 is responsible for hypercortisolism in adipose tissue and liver and has been implicated in the pathogenesis of abdominal obesity, metabolic syndrome and type 2 diabetes. The article summarizes recent progress in the discovery and development of small molecule inhibitors of 11β-HSD1. The article highlights the medicinal chemistry, SAR, in vivo pharmacodynamic effects, and efficacy of a few representative classes of inhibitors in models of diabetes. Furthermore, the authors also review the structural characteristics of each class of inhibitors by analyzing the inhibitor cocrystal structures of 11β-HSD1. The final review by Ho, Kulkarni and Lee focuses on the development of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors as potential antidiabetic therapeutics. SGLT2 is a high-capacity, low-affinity transporter responsible for approximately 90% of glucose reabsorption in the kidney. Genetic as well as pharmacological data indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. The review summarizes a number of disclosed SGLT2 inhibitors, including their structure-activity relationships (SARs) studies, their selectivity against SGLT1, and the most updated phase III clinical data of SGLT2 inhibitor, dapapgliflozin. We would like to offer our deep appreciation to all the authors contributing to this issue; without whom this collection would not be possible. We would also like to express our sincere gratitude to Dr. Allen Reitz and Dr. Rhoda Weber Joseph for the invitation to be the Guest Editor to compile this issue, and the reviewers for being meticulous in their evaluation of the manuscript.