Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective β3-adrenergic receptor agonists

Abstract 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 phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human β3-, β2-, and β1-ARs. Several of the analogues ( 21a , 21b , and 27a ) exhibited potent agonistic activity at the β3-AR. Among the compounds described herein, the N -methyl-1-benzylimidazol-2-ylacetanilide derivative ( 21b ) was found to be the most potent and selective β3-AR agonist, with an EC 50 value of 0.28 μM and no agonistic activity for either the β1- or β2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.