Discovery of novel thiourea derivatives as potent and selective beta3-adrenergic receptor agonists

  • Bioorg Med Chem. 2009 Aug 1;17(15):5510-9. doi: 10.1016/j.bmc.2009.06.031.
Tatsuya Maruyama  1 ,  Norio Seki ,  Kenichi Onda ,  Takayuki Suzuki ,  Souichirou Kawazoe ,  Masahiko Hayakawa ,  Tetsuo Matsui ,  Toshiyuki Takasu ,  Mitsuaki Ohta
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. [email protected]
PMID: 19581100 DOI: 10.1016/j.bmc.2009.06.031
Abstract

In the search for potent and selective human beta3-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 beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.