R. Sarges et al., GLUCOSE TRANSPORT-ENHANCING AND HYPOGLYCEMIC ACTIVITY OF 2-METHYL-2-PHENOXY-3-PHENYLPROPANOIC ACIDS, Journal of medicinal chemistry, 39(24), 1996, pp. 4783-4803
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/k
g. The mechanism of action of these drugs may involve enhanced glucose
transport, especially in fat cells, but the compounds do not stimulat
e 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 d
ecrease hepatocyte gluconeogenesis in vitro, but this is not likely to
be a major contributor to the hypoglycemic effect observed in vivo. L
ikewise, a modest decrease in food consumption observed with some of t
hese compounds was shown by a pair-feeding experiment not to be the pr
imary cause of the hypoglycemia observed.