Discovery of novel thiourea derivatives as potent and selective beta3-adrenergic receptor agonists.
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.
Maruyama
Tatsuya
T
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. tatsuya.maruyama@jp.astellas.com
Seki
Norio
N
Onda
Kenichi
K
Suzuki
Takayuki
T
Kawazoe
Souichirou
S
Hayakawa
Masahiko
M
Matsui
Tetsuo
T
Takasu
Toshiyuki
T
Ohta
Mitsuaki
M
D000322:Adrenergic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D058673:Adrenergic beta-3 Receptor Antagonists; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D050198:Phenoxypropanolamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D000322:Adrenergic Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D007004:Hypoglycemic Agents; D050198:Phenoxypropanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D013890:Thiourea