Current and Future Drug Targets in Weight Management with thyroid preparations, ephedrine, dinitrophenol, etc. Despite many efforts to bring new compounds to the market, the intestinal lipase inhibitor orlistat has remained the only compound that is currently approved both in the US and in Europe. However, some new drugs appear to be close to approval, and it is obvious that the pharmacology of weight management remains a highly challenging area for industry and academia. It also represents a multi-billion- dollar market, and several research groups are heavily engaged in finding new targets and molecules. The history of discovery of anti-obesity drugs is also characterized by much serendipity. As described further, some of the most advanced preparations currently in the pipeline are based on compounds or drug targets that were originally found for other indications. STRATEGIES TO REDUCE ENERGY (RE-)ABSORPTION Reducing the uptake of energy-rich molecules from the GI tract, preferably by locally acting compounds, could be an attractive approach, since this would minimize the risks of systemic side-effects. Indeed, the lipase inhibitor orlistat belongs to the very few compounds having survived so far. This is also a suggested mechanism of action of many food supplements advertised for weight management. Several of these preparations claim to bind fat in the GI tract, including chitosan, glucomannan, psyllium seeds, etc. However, there seems to be little evidence for sustained efficacy in humans of these products (37). A new lipase inhibitor, cetilistat, is now in an advanced stage of Fig. 2 Chemical structures of the lipase inhibitors orlistat (an ap- proved drug) and cetilistat (currently in development). 1795 development. In addition, a number of new targets are evolving, including inhibitors of Microsomal Triglyceride t r a n s f e r P r o t e i n ( M T P ) a n d D i a c y l g l y c e r o l O - acyltransferase (DGAT). A related but different category comprises the inhibitors of low-affinity sodium-dependent glucose co-transporters (SGLT2). Acting by blocking glucose re-absorption in the kidneys and originally devel- oped for diabetes, some are now in trials for obesity. Farther on the horizon are strategies aiming to modulate GI metabolism. Inhibitors of Pancreatic Lipase Pancreatic lipase is one of the exocrine enzymes of pancreatic juice and is essential for digestion and absorption of dietary fats. Orlistat (Fig. 2) is the tetrahydro-derivative of the natural compound lipstatin, produced by the microor- ganism Streptomyces toxytricini (38). Orlistat has shown to be effective in reducing body weight, leading to 5–10% weight loss in 50–60% of patients. In clinical trials, this loss (and related clinical benefits) has shown to be maintained up to at least four years. A typical side effect of the compound is steatorrhoea (fecal fat loss). The compound is also sold in an OTC preparation in a lower dose compared to the prescription form. Recently, concerns have been raised concerning potential liver damage in orlistat users. In August 2009, the FDA posted an early communication about an ongoing safety review on orlistat (39). Cetilistat (= ATL-962, Fig. 2) is a newly developed lipase inhibitor which has recently entered phase III clinical testing. It has been suggested that the compound is equally effective as orlistat while producing fewer GI side effects