Synthesis and Evaluation of Novel Phenylethanolamine Derivatives containing Acetanilides as Potent and Selective .BETA.3-Adrenergic Receptor Agonists

In the search for potent and selective human beta(3)-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human beta 3-, beta 2-, and beta 1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthiazol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3-ylacetanilide (36h) derivatives showed potent agonistic activity at the beta 3-AR with functional selectivity over the beta 1- and beta 2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent diabetic model.