(4-Piperidin-1-yl)phenyl Amides: Potent and Selective Human β3 Agonists

In search of potent and selective human β 3 agonists as potential drugs for the treatment of human obesity and type II diabetes, a series of (4-piperidin-1-yl)phenyl amides was prepared and evaluated for their biological activity on the human β 3 -adrenergic receptor. The leucine derivative 26e and the reverse amide 33b were found to be the two most potent and selective compounds in this study. With EC 50 values of 0.008 and 0.009 μM, respectively, at the β 3 receptor, nearly completely abolished intrinsic activity at either the β 1 or β 2 receptor, and significant thermogenesis effects on human β 3 -adrenergic receptor transgenic mice, 26e and 33b are among the most potent and selective human β 3 agonists known to date.