Development of beta(3)-adrenoceptor agonists as antiobesity and antidiabetes drugs in humans: Current status and future prospects

The discovery of a third P-adrenergic receptor (beta (3)-AR) in the early 1 980s and the finding that stimulation of this receptor by selective agonist s leads to marked weight loss and glycemic improvements in rodent models of obesity and diabetes, respectively, has led to intensive research efforts to develop beta (3)-AR agonists for the treatment of obesity and Type 2 dia betes in humans. Indeed, the ability of beta (3)-AR agonists to simultaneou sly increase lipolysis, fat oxidation, energy expenditure, and insulin sens itivity suggests that this class of agents may have promising potential as both antiobesity and antidiabetic agents. Unfortunately, several pharmaceut ical problems have hampered their development as therapeutic agents in huma ns over the past 15 years. Major obstacles have been the pharmacological di fferences between the rodent and human beta (3)-AR, the lack of selectivity of previous compounds for the beta (3) over beta (1)/ beta (2)-ARs, and un satisfactory pharmacokinetic properties. More recently, clinical studies wi th a highly (rodent-) selective beta (3)-AR agonist have provided unequivoc al evidence that selective beta (3)-AR stimulation can increase lipolysis, fat oxidation, and insulin sensitivity in humans. Meanwhile, cloning of the human beta (3)-AR has allowed the development of novel compounds that are specifically targeted at the human receptor. This new generation of compoun ds has shown promising results in nonhuman primates and in Phase 1 studies in humans. Once human beta (3)-AR selective compounds with satisfactory pha rmacokinetic properties become available, clinical testing will reveal whet her their effects are sufficient and safe in the long term to allow the use of these agonists for the treatment of obesity and diabetes in humans. (C) 2000 Wiley-Liss, Inc.