Current and Future Drug Targets in Weight Management 1811 Fig. 15 Chemical structures of thyroid hormone (T3) and 2 selective thyroid hormone receptor (TR) subtype β-agonists developed as anti- obesity and/or lipid-lowering agents. affinity ligand cortisol (or corticosterone in rodents) (150,151). It is rather ubiquitously expressed throughout the body, with highest levels in the liver followed by adipose tissue and brain. Several natural compounds of both endogenous and exogenous origin are known inhibitors of 11β-HSD1, including glycyrrhetinic acid from licorice root and its synthetic hemisuccinyl ester, carbenoxolone (151). However, most of these are unspecific, whilst enzyme and also tissue specificity would be important prerequisites for therapeutic usefulness in obesity and/or its metabolic complications. Selective 11β- HSD1 inhibitors that are effective in adipose tissue have shown positive results in animal models and may also be efficacious in improving insulin sensitivity and reducing weight in humans (150– 152). Several companies, including Biovitrum, Amgen, AstraZeneca, Abbott, Merck, Pfizer, and Incyte have developed 11β-HSD1 inhibitors, mainly for treatment of type 2 diabetes but also for obesity (153–155). Some structures are given in Fig. 16. Although the development of the first selective 11β- HSD1 inhibitor BVT-3498 (AMG-331) was terminated during phase II testing, several other compounds have reached the clinical phase. One of the most advanced is INCB 13739 (structure not disclosed) from Incyte (156). The next few years will be pivotal in showing whether this target will be successful. The need for selectivity and the risk of activation of the HPA axis have been suggested as potential hurdles (154). Sirtuin 1 as Potential Target in Obesity SIRT1 belongs to the silent information regulator 2 (Sir2) enzymes (or sirtuins) which have emerged as central players in the regulation of critical metabolic pathways, such as insulin secretion and lipid metabolism. Sirtuins regulate their targets by modulating the activity of their partner proteins through reversible de-acetylation. The most studied sirtuin is SIRT1 (see for example (157) and (158) for recent reviews). This enzyme has been implicated in longevity and the beneficial effects of caloric restriction. SIRT1 enhances fat mobilization and lipolysis by binding to and repressing the expression of PPARγ-regulated genes, including those mediating fat storage. In addition, SIRT1 interacts with PGC-1α, inducing the expression of mitochondrial genes involved in oxidative metabolism and fatty acid oxidation. Resveratrol (Fig. 17) has been proposed as a natural SIRT1 activator, in addition to having other activities. Following the discovery of SIRT1 and its role in metabolism, several small-molecule SIRT1 activators (some examples given in Fig. 17) have been synthesized with structures different from that of resveratrol but with considerably higher potency (159,160). A number of these compounds were reported to improve metabolic function in animal models of diabetes and obesity, suggesting that they may have therapeutic potential. For example, SIRT 1720 (Fig. 17) was found to protect mice against diet-induced obesity by enhancing oxidative metabolism in skeletal muscle, liver and BAT (161). In 2004, GlaxoSmithKline founded Sirtris Pharmaceut- icals, a company focusing on the development of drugs targeting SIRT1. Sirtris reports a number of compounds in clinical development (162). However, recently Pacholec et al. (163) suggested that resveratrol and a number of the Sirtris compounds are not directly activating SIRT1. The authors also questioned the beneficial effects of SRT1720 in a rodent diabetes model and stated that the Sirtris compounds and resveratrol are highly promiscuous com- pounds having multiple targets. Similar to several other classes described in this review, the coming years will show whether the high expectations are justified. Diazoxide Diazoxide (Fig. 18) is a potassium channel activator that opens the K+- ATP channels in pancreatic β-cells, thereby inhibiting insulin secretion. Diazoxide is currently used to treat hypoglycemia but may also have potential in hyper- triglyceridemia and obesity. Although some investigators suggest a beneficial effect of diazoxide in obesity in combination with caloric restriction and physical exercise (164), its usefulness as a target in obesity is questioned by others (165). A controlled release