Hu B, Ellingboe J, Han S, Largis E, Mulvey R, Oliphant A, Sum F W, Tillett J
Chemical Sciences and Cardiovascular/Metabolic Diseases Research, Wyeth-Ayerst Research, Pearl River, New York 10965, USA.
J Med Chem. 2001 Apr 26;44(9):1456-66. doi: 10.1021/jm000544b.
In search of potent and selective human beta(3) agonists as potential drugs for the treatment of human obesity and type II diabetes, a series of (4-piperidin-1-yl)phenyl amides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor. The leucine derivative 26e and the reverse amide 33b were found to be the two most potent and selective compounds in this study. With EC(50) values of 0.008 and 0.009 microM, respectively, at the beta(3) receptor, nearly completely abolished intrinsic activity at either the beta(1) or beta(2) receptor, and significant thermogenesis effects on human beta(3)-adrenergic receptor transgenic mice, 26e and33b are among the most potent and selective human beta(3) agonists known to date.
为寻找强效且具选择性的人β(3)激动剂作为治疗人类肥胖症和II型糖尿病的潜在药物，制备了一系列(4-哌啶-1-基)苯基酰胺，并评估了它们对人β(3)-肾上腺素能受体的生物活性。在本研究中，亮氨酸衍生物26e和反向酰胺33b被发现是两种最具强效和选择性的化合物。在β(3)受体处的EC(50)值分别为0.008和0.009微摩尔，在β(1)或β(2)受体上几乎完全消除内在活性，并且对人β(3)-肾上腺素能受体转基因小鼠具有显著的产热效应，26e和33b是迄今为止已知的最具强效和选择性的人β(3)激动剂。
