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ENDOCRINE AND DIABETES

Identification of Novel Orally Available Small Molecule Insulin Mimetics

Veterans Affairs San Diego Healthcare System and the Veterans Medical Research Foundation, San Diego, California (B.L., N.J.G.W.); Department of Chemistry, University of California, Riverside, California (Z.L., K.P., L.D., M.C.P.); and Moore's Cancer Center and the Department of Medicine, University of California at San Diego, La Jolla, California (A.P., L.Z., N.J.G.W.)

Oral hypoglycemic agents have great potential for the treatment of both type 1 and type 2 diabetes. Here we report the identification of novel, small-molecule, insulin mimetics that activate the insulin receptor (IR) in vivo and in vitro, stimulate the Akt and extracellular signal-regulated kinase pathways downstream of the IR, and mimic the ability of insulin to stimulate glucose uptake, glycogen synthesis, and lipid synthesis in 3T3-L1 adipocytes. However, the compounds do not mimic the mitogenic effect of insulin. In animals, these compounds have oral hypoglycemic effects in both normal C57BL6 mice and diabetic db/db mice. Quantitative structure activity relationship modeling on data from a library of 60 compounds has highlighted structural features that are important for IR agonist activity that can be used to guide design of second and third generation compounds with greater potency and specificity.

Address correspondence to: Dr. Nicholas J. G. Webster, Stein Clinical Research Bldg. 201, Department of Medicine (0673), University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673. E-mail: nwebster{at}ucsd.edu