Sarges R, Hank R F, Blake J F, Bordner J, Bussolotti D L, Hargrove D M, Treadway J L, Gibbs E M
Pfizer Central Research, Pfizer Inc., Groton, Connecticut 06340, USA.
J Med Chem. 1996 Nov 22;39(24):4783-803. doi: 10.1021/jm950364f.
A series of 2-phenoxy-3-phenylpropanoic acids has been prepared which contains many potent hypoglycemic agents as demonstrated by assessing glucose lowering in ob/ob mice. Some compounds (32, 33, 59) normalize plasma glucose in this diabetic model at doses of approximately 1 mg/kg. The mechanism of action of these drugs may involve enhanced glucose transport, especially in fat cells, but the compounds do not stimulate GLUT4 translocation and do not increase the levels of GLUT1 or GLUT4 in vivo. Thus, these compounds may enhance the intrinsic activity of the glucose transporter GLUT1 or GLUT4. Some compounds also modestly decrease hepatocyte gluconeogenesis in vitro, but this is not likely to be a major contributor to the hypoglycemic effect observed in vivo. Likewise, a modest decrease in food consumption observed with some of these compounds was shown by a pair-feeding experiment not to be the primary cause of the hypoglycemia observed.
已经制备了一系列2-苯氧基-3-苯基丙酸，其中包含许多强效降糖剂，这通过评估ob/ob小鼠的血糖降低情况得到了证实。一些化合物（32、33、59）在约1mg/kg的剂量下可使该糖尿病模型的血糖正常化。这些药物的作用机制可能涉及增强葡萄糖转运，尤其是在脂肪细胞中，但这些化合物不会刺激GLUT4易位，也不会在体内增加GLUT1或GLUT4的水平。因此，这些化合物可能增强葡萄糖转运蛋白GLUT1或GLUT4的内在活性。一些化合物在体外也能适度降低肝细胞糖异生，但这不太可能是体内观察到的降糖作用的主要原因。同样，通过配对喂养实验表明，其中一些化合物观察到的食物摄入量适度减少并非所观察到的低血糖的主要原因。
