Discovery of novel thiourea derivatives 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, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human β3-, β2-, and β1-ARs. Among these compounds, 4-nitrophenylthiourea ( 18i ) and 3-methoxyphenylthiourea ( 18k ) derivatives were found to exhibit potent agonistic activity at the β3-AR, with EC 50 values of 0.10 and 0.16 μM, respectively, and no agonistic activity for either the β1- or β2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.