Discovery of novel thiourea derivatives 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 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 beta 3-, beta 2-, and beta 1-ARs. Among these compounds, 4-nitrophenylthiourea ( 18i) and 3- methoxyphenylthiourea ( 18k) derivatives were found to exhibit potent agonistic activity at the beta 3-AR, with EC sub(50) values of 0.10 and 0.16 mu M, respectively, and no agonistic activity for either the beta 1- or beta 2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.