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

Abstract

The discovery of a third p-adrenergic receptor (β 3 -AR) in the early 1980s and the finding that stimulation of this receptor by selective agonists leads to marked weight loss and glycemic improvements in rodent models of obesity and diabetes, respectively, has led to intensive research efforts to develop β 3 -AR agonists for the treatment of obesity and Type 2 diabetes in humans. Indeed, the ability of β 3 -AR agonists to simultaneously increase lipolysis, fat oxidation, energy expenditure, and insulin sensitivity suggests that this class of agents may have promising potential as both antiobesity and antidiabetic agents. Unfortunately, several pharmaceutical problems have hampered their development as therapeutic agents in humans over the past 15 years. Major obstacles have been the pharmacological differences between the rodent and human β 3 -AR, the lack of selectivity of previous compounds for the β 3 - over β 1 / β 2 -ARs, and unsatisfactory pharmacokinetic properties. More recently, clinical studies with a highly (rodent-) selective β 3 -AR agonist have provided unequivocal evidence that selective β 3 -AR stimulation can increase lipolysis, fat oxidation, and insulin sensitivity in humans. Meanwhile, cloning of the human β 3 -AR has allowed the development of novel compounds that are specifically targeted at the human receptor. This new generation of compounds has shown promising results in nonhuman primates and in Phase 1 studies in humans. Once human β 3 -AR selective compounds with satisfactory pharmacokinetic properties become available, clinical testing will reveal whether 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.