Glucose Transport-Enhancing and Hypoglycemic Activity of 2-Methyl-2-phenoxy-3-phenylpropanoic Acids

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-11, Vol.39 (24), p.4783-4803
Main Authors: Sarges, Reinhard, Hank, Richard F, Blake, James F, Bordner, Jon, Bussolotti, Donald L, Hargrove, Diane M, Treadway, Judith L, Gibbs, E. Michael
Format: Article
Language:English
Subjects:
Animals
Benzopyrans - pharmacology
Biological and medical sciences
Blood Glucose - drug effects
Cells, Cultured
Deoxyglucose - metabolism
General and cellular metabolism. Vitamins
Glucagon - pharmacology
Gluconeogenesis - drug effects
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - pharmacology
Liver - drug effects
Magnetic Resonance Spectroscopy
Medical sciences
Mice
Mice, Inbred Strains
Models, Molecular
Molecular Conformation
Molecular Structure
Monosaccharide Transport Proteins - drug effects
Monosaccharide Transport Proteins - metabolism
Pharmacology. Drug treatments
Phenylpropionates - chemical synthesis
Phenylpropionates - pharmacology
Rats
Thiazoles - pharmacology
Thiazolidinediones
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm950364f