Agents which reduce body weight have been actively sought after for many decades. Early animal-based feeding models were most commonly used to evaluate anorectic agents (appetite suppressants) or general metabolic stimulants. The amphetamine-type mechanism is now disfavored, because of the associated risks of abuse and chemical dependence. Activation of serotonergic systems either by direct activation of serotonin receptor subtypes or by inhibiting serotonin reuptake (SSRIs) has proved successful. Nevertheless, the exact receptor subtype profile that is required is not known, so that it is very difficult to design a drug discovery program based on this approach. It is more reasonable to explore obesity as a possible therapeutic indication for a serotonin-based compound developed for another purpose. In general, the adventitious finding of weight loss during the clinical trials of any compound should be considered as a possible opportunity for further development. The valvular heart disease seen with fenfluramine was a disappointment. In general, extreme caution regarding possible cardiovascular complications is needed for patients already at risk based on their high BMI. Further, drugs for non-insulin-dependent diabetes need to be carefully monitored for their effects on body weight because of the high correlation of diabetes with obesity. Due to the chronic nature of treatment, antiobesity drugs must have a high margin of safety relative to side effects that may emerge. The value of human β3-adrenoceptor agonists will become apparent once data are available from relevant clinical evaluations. These data will help researchers to determine whether the needed separation from cardiovascular side effects is possible. It is risky to start new human β3- adrenoceptor drug discovery programs now unless these clinical results are favorable. Modulation of satiety factors such as CCK or bombesin is not a prime strategy because the control of feeding is incredibly redundant. Inhibition of meal size is often compensated by an increase in the number of meals. Newer approaches are attractive, partly because they have the allure that their deficiencies are not yet apparent. Nevertheless, we believe that there is great promise in several of these. Specifically, NPY receptor antagonists and MC-4 receptor agonists appear to act at a more fundamental level than satiety factors and might be useful as therapeutics. The challenge in modern drug discovery is not only obtaining high affinity receptor ligands but also achieving desirable pharmacokinetic properties such as high oral bioavailability and long half-life suitable for chronic use. The uncoupling proteins are more likely to remain secondary mechanisms by which antiobesity compounds act in part and not themselves a primary target for intervention. PPARγ antagonists may prove useful, unless metabolic side effects such as hyperglycemia interfere. There is a wealth of new research in the area of obesity which lends credence to the view that there will be a variety of effective and mechanism-based antiobesity drugs introduced into clinical practice in the coming decades. With the growing incidence of obesity due to an increasingly sedentary lifestyle, these drugs, when used properly and under responsible medical supervision, could increase the length and quality of life for many people. Given the large genetic component of obesity, one can imagine that phenotyping of individuals, both in clinical trials and in broad clinical practice, will offer the greatest chance for effective therapy. With increasing use of the tools of molecular biology, additional targets for obesity will be discovered such as orexin and its receptors. These new approaches may then be evaluated using high-throughput screening of large compound libraries and combinatorial chemistry or parallel synthesis, to obtain selective agents for further evaluation. There is every reason to believe that medicinal chemists will be able to make a significant contribution to the discovery of new and useful therapeutic agents for the treatment of obesity.
