Maruyama Tatsuya, Onda Kenichi, Hayakawa Masahiko, Seki Norio, Takahashi Takumi, Moritomo Hiroyuki, Suzuki Takayuki, Matsui Tetsuo, Takasu Toshiyuki, Nagase Itsuro, Ohta Mitsuaki
Drug Discovery Research, Astellas Pharma Inc, Tsukuba, Ibaraki, Japan.
Bioorg Med Chem. 2009 May 1;17(9):3283-94. doi: 10.1016/j.bmc.2009.03.044. Epub 2009 Mar 27.
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, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.
在寻找强效且具选择性的人类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（II型）糖尿病的潜在药物的过程中，制备了一系列含乙酰苯胺的新型苯氧丙醇胺衍生物，并在人类β3 -、β2 - 和β1 - 肾上腺素能受体上评估了它们的生物活性。其中一些类似物（21a、21b和27a）在β3 - 肾上腺素能受体上表现出强效激动活性。在本文所述的化合物中，N - 甲基 - 1 - 苄基咪唑 - 2 - 基乙酰苯胺衍生物（21b）被发现是最具强效和选择性的β3 - 肾上腺素能受体激动剂，其半数有效浓度（EC50）值为0.28微摩尔，对β1 - 或β2 - 肾上腺素能受体均无激动活性。此外，21b在啮齿动物糖尿病模型中显示出显著的降血糖活性。
