Discovery of novel thiourea 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, 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 EC50 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.

Among a novel series of thiourea derivatives synthesized and evaluated for agonistic activities at the human β-ARs, compound 18k was found to be the most potent and selective β3-AR agonist with oral hypoglycemic activity in diabetic kk mice.Figure optionsDownload as PowerPoint slide