Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 24, Pages 8096-8108Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8008713
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Funding
- Hebrew University
- Deutch Foundation for Applied Sciences
- Alex Grass Center for Drug Design and Synthesis of Novel Therapeutics
- David R. Bloom Center for Pharmacy at The Hebrew University School of Pharmacy
- Nophar Program of the Israel Ministry of Commerce and Trade
- Israel Science Foundation of The Israel Academy of Sciences and Humanities
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Type 2 diabetes mellitus has reached epidemic proportions; therefore, the search for novel antihyperglycemic drugs is intense. We have discovered that D-Xylose increases the rate of glucose transport in a non-insulin-dependent manner in rat and human myotubes in vitro. Due to the unfavorable pharmacokinetic properties Of D-Xylose we aimed at synthesizing active derivatives with improved parameters. Quantitative structure-activity relationship analysis identified critical hydroxyl groups in D-xylose. These data were used to synthesize various hydrophobic derivatives Of D-Xylose of which compound 19 the was most potent compound in stimulating the rate of hexose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of myotubes. This effect resulted from the activation of AMP-activated protein kinase without recruiting the insulin transduction mechanism. These results show that lipophilic D-Xylose derivatives may serve as prototype molecules for the development of novel anti hyperglycemic drugs for the treatment of diabetes.
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