Discovery of novel acetanilide derivatives as potent and selective β3-adrenergic receptor agonists

In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the β3-AR with functional selectivity over the β1- and β2-ARs. In particular, compound 2u was found to be the most potent and selective β3-AR agonist with an EC50 value of 0.11 μM and no agonistic activity for either the β1- or β2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

Graphical abstract Among a novel series of acetanilide derivatives synthesized and evaluated for agonistic activities at the human b-ARs, compound 2u was found to be the most potent and selective b3-AR agonist.Figure optionsDownload full-size imageDownload as PowerPoint slide