Abstract
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.
Footnotes
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This work was supported by the American Diabetes Association (to M.C.P.) and the National Institutes of Health (Grant R03 AG023191) (to N.J.G.W.). L.Z. was supported by a fellowship from Merck Pharmaceuticals. N.J.G.W. is a faculty member of the UCSD Biomedical Sciences Graduate Program. A.P. is a student at the UCSD School of Medicine.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126102.
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ABBREVIATIONS: DAQ-B1, demethylasterriquinone-B1, 2-[2-(1,1-dimethyl-allyl)-1H-indol-3-yl]-3,6-dihydroxy-5-[7-(3-methyl-but-2-enyl)-1H-indol-3-yl]-[1,4]benzoquinone; ZL-196, 2,5-dihydroxy-3-(7-(3-methyl-but-2-enyl)-1H-indol-3-yl)-[1,4]-benzoquinone; ZL-202, 2,5-dihydroxy-3-[2-(1,1-dimethyl-allyl)-1H-indol-3-yl]-[1,4]-benzoquinone; LD-17, 2,5-dihydroxy-3-(7-benzyloxy-1H-indol-3-yl)-[1,4]-benzoquinone; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Cpd.2, 3,6-dihydroxy-2-(1-methyl-indol-3-yl)-5-phenyl-[1,4]-benzoquinone; QSAR, quantitative structure activity relationship; ELISA, enzyme-linked immunosorbent assay; IR, insulin receptor; IGF, insulin-like growth factor-1; CHO, Chinese hamster ovary; ERK, extracellular-regulated kinase; GST, glutathione transferase; hIRCB, rat 1 fibroblasts overexpressing the human IR; KRP, Krebs-Ringer phosphate; LD-20B, 2,5-dihydroxy-3-(5-methyl-1H-indol-3-yl)-[1,4]-benzoquinone; ZL-194, 2,5-dihydroxy-3-(N-methyl-indol-3-yl)-[1,4]-benzoquinone.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received May 22, 2007.
- Accepted August 7, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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