Maruyama Tatsuya, Onda Kenichi, Suzuki Takayuki, Hayakawa Masahiko, Takahashi Takumi, Matsui Tetsuo, Takasu Toshiyuki, Nagase Itsuro, Ohta Mitsuaki
Drug Discovery Research, Astellas Pharma Inc, Ibaraki 305–8585, Japan.
Chem Pharm Bull (Tokyo). 2012;60(5):647-58. doi: 10.1248/cpb.60.647.
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human β3-, β2-, and β1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl)acetamide (4 g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the β3-AR with functional selectivity over the β1- and β2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.
在寻找强效且具选择性的人β3-肾上腺素能受体（AR）激动剂作为治疗肥胖症和非胰岛素依赖型（2型）糖尿病潜在药物的过程中，制备了一系列带有苯氧丙醇胺部分的N-苯基-（2-氨基噻唑-4-基）乙酰胺，并评估了它们对人β3-、β2-和β1-AR的生物活性。在这些化合物中，N-苯基-（2-苯基氨基噻唑-4-基）乙酰胺（4g）、N-苯基-（2-苄基氨基噻唑-4-基）乙酰胺（4j）和N-苯基-[2-（3-甲氧基苯基）氨基噻唑-4-基]乙酰胺（6g）衍生物对β3-AR显示出强效激动活性，且对β1-和β2-AR具有功能选择性。此外，这些化合物在糖尿病啮齿动物模型中表现出显著的降血糖活性。
